The basis of the "What If?" series is to give Marvel fans a glimpse into the road less travelled by their favorite and not-so-favorite heroes with mild to moderate success. It's also worth noting that, ninety percent of the time, "What If?" stories don't have a happy ending.
Previously in "What If?", Spider-Man joined the Fantastic Four, making it the Fantastic Five. However, at the end of that story, Sue left the team, making it once again the Fantastic Four. In the intervening time, however, Sue has rejoined the team and was impregnated by Reed Richards. Thus our story begins, after Uatu has his say.
The book begins with Uatu telling us about the Time Keeper's plot involving Immortus and his culling of divergent realities. The plot succeeded to a point, failing only after the intervention of the West Coast Avengers. However, the Time Keepers are up to their old tricks, and are letting Uatu take a front row seat.
The story of "What If the Fantastic Five Had Invaded the Negative Zone?" begins with the male members of the team sitting at the Baxter Building asking Reed if he should be at the hospital with Sue, who is about to deliver a baby. Reed snaps at them, and then reveals that the accident that gave the original Fantastic Four their powers may now mean the death of Sue and her unborn child. The only thing that can save them is a rare element that can only be found in the Negative Zone, where Reed plans to go alone.
The rest of the FF won't have it, and soon the team straps on harnesses and are off to the Negative Zone. At this point, however, the Watcher announces his confusion, as Sue should be with Namor at this point, not lying in a hospital bed with Reed's unborn child. The Time Keepers aim to keep that child unborn, and Uatu asks them why. The answer: ANNIHILUS, THE LIVING DEATH THAT WALKS! One of Annihilus' scavengers swoops in and grabs Spider-Man, only to toss him on a rock a few minutes later. The rock is actually a magnet, and it's dragging Spider-Man towards it due to this harness. Soon the web-slinger is knocked out, and when he comes to, he discovers that he is the prisoner of Annihilus.
The Living Death that Walks aims to study Spider-Man, who valiantly attacks him so the Fantastic Five can complete their mission. The attack is futile, and now Annihilus knows of their mission. Spider-Man refuses to tell him, as he too does not know, and soon Annihilus begins blasting him with the Cosmic Control Rod. The wall-crawler dodges the blasts, then blinds Annihilus with webbing. Taking advantage of his adversary's ailment, Spider-Man steals the Cosmic Control Rod away from Annihilus and makes a break for it.
Meanwhile, the rest of the Fantastic Five are searching for the web-slinger, and they fall victim to some sort of living transparent spheroid. They're deposited in a room with a sponge, a robot, and a saw. Mister Fantastic, the Thing, and the Human Torch utilize teamwork to stay alive and are about to strike back against the trio of foes when suddenly the robot, sponge, and saw are vaporized! Spider-Man has saved his comrades, and gotten the rare element Reed needs to save his unborn child, to boot. The team then moves to return to Earth.
Uatu is telling the Time Keepers how Sue's child was saved in nearly every reality, and if anything, the only thing that changed was that Spider-Man caused the Cosmic Control Rod to be stolen much sooner. The Time Keepers still aim to see that the child remains unborn, and they enlist Doctor Doom to attack the Fantastic Five. He'll have to wait his turn, however, as Annihilus wants his rod back.
They easily escape Annihilus due to the control rod, but at the team's inter- dimensional craft, Doctor Doom is waiting. He takes out Reed Richards and swipes the control rod, then leaves the rest of the team to their fate as they move towards anti-matter. Back on Earth, Sue is still in labor and pain. Then we cut back to the Negative Zone where Doom and Annihilus are throwing down over the Cosmic Control Rod. We cut away from their fate to the Fantastic Five drifting towards their doom on a rock, where we're treated to a bit of exposition.
Apparently, Sue had married Namor, but for some reason returned her to the surface world and Reed. The Sub-Mariner had also undone the process that made her an Atlantean. However, there's still the fight between Doom and Annihilus going on. A being in a cloak pulls Doom's astral form out of his body, and tells it that the Time Keepers lied to him. The being, calling itself the Whisperer, tells Doom that if Reed doesn't get the Cosmic Control Rod back, it will mean the end of the world! Doom somehow knows the Whisperer is being truthful, and when his astral form is returned to his body, Doom tosses the Cosmic Control Rod to Reed.
Annihilus is understandably miffed about this turn of events, and fights Doom with renewed vigor. However, as Annihilus is blinded with rage, he doesn't see that the pair are about to hit the Anti-Matter planet and explode.
The Fantastic Five are now eagerly awaiting the birth of Reed and Sue's son. It happens, and everyone is happy for Sue and Reed, and they all pledge to protect Franklin Richards from whatever dangers may threaten him.
The Time Keepers are a bit angry at this turn of events, but figure they still have three universes to try and destroy. They don't understand why Doom sacrificed himself, however. Uatu tells us that at the last minute, the Whisperer appeared and rescued Doom from his fate for an unknown purpose...