Fullmetal Alchemist: Brotherhood is a retelling of the story based off the manga, and is not directly related to the first Fullmetal Alchemist series. Edward and Alphonse Elric are two brothers living in a world where the practice of alchemy flourishes. After their mother passes away, the brothers work together to try and bring her back using alchemy, but without success. Their failure results in Edward losing his left leg and right arm, while Alphonse loses his entire body and has his soul attached to a suit of armor.
As Ed, Al and Winry arrive in Rush Valley, Ed's State Alchemist Watch is stolen by a pickpocket named Paninya, who has automail legs. After tracking her down, Winry asks her automail's creator, Mr. Dominic, to let her be his apprentice, but is swiftly declined. As Winry convinces Paninya to stop pickpocketing and return the watch, she peeks in it and finds, carved inside, the date Ed and Al burned down their house.
Ed and Al decide to go to the town of Dublith to visit their alchemy teacher, Izumi Curtis, to ask her for information about the Philosopher's Stone. They agree to take Winry with them when she notices that Rush Valley, a town best known for its automail shops, is on the way to Dublith. King Bradley appears and warns the Elrics to be careful around the military, and he then hops out of a window to evade his subordinates. Hughes investigates the problems in Lior, The Fifth Laboratory, and the war in Ishbal. He discovers a connection, but is then attacked by Lust...
Ed and Al are in hospital following the Fifth Laboratory incident. Ross slaps Ed for being reckless, and asks him to trust adults more. Needing his automail repaired, Ed calls for Winry to come to Central. When Winry arrives at the train station, Al contemplates what Barry had told him. Hughes invites Winry over to his daughter's birthday party, where she laments that Ed and Al never tell her anything. Hughes tells her that men tend to hide things so as not to worry anyone. Al decides to confront Ed about what he was afraid to tell him, asking if he was really an artificial soul...
Outside the lab, Al fights Barry the Chopper, and Ed faces Slicer inside. It is revealed that both opponents are souls of murderers affixed to armor. Ed struggles in his battle when his automail arm malfunctions, the result of Winry forgetting to add a small bolt back in Resembool. Ed is particularly troubled when his opponent turns out to be a pair of brothers, each controlling a different part of the armor. Al initially has the advantage in his fight, until Barry suggests that Al never existed and was just a doll made by Ed. Al contemplates this as a possibility, since Ed had previously mentioned to Al that he had something he was afraid to tell him.
Ed and Al arrive back in Central, only to find that the First Branch Library had been burned to the ground. Scar encounters and battles Lust and Gluttony in the sewers, resulting in a large explosion. Ed and Al's new escorts, Maria Ross and Denny Brosh, direct Ed and Al to Sheska, a file clerk who had worked at the First Branch, but was fired for spending all her time reading. Sheska reveals that she has memorized all of Marcoh's works, and then makes hand-written duplicates for the Elrics.