Among the most controversial episodes surrounding Nero's rise is undoubtedly his alleged role in the poisoning of his half-brother, the son of Emperor Claudius and his third wife, Messalina. Born Tiberius Claudius Caesar Germanicus, the honorific title of Britannicus was bestowed upon him by his father two years after his birth. Claudius, in fact, refused the same title offered to him by the Senate for the conquest of Britain and decided to bestow it on his son.

Following the death of Claudius—who was said to have been poisoned by his niece and wife, Agrippina, with mushrooms he favoured—Nero was acclaimed the new princeps. Nero had previously been adopted by Claudius at Agrippina's urging. This adoption effectively ousted Britannicus, who, at just twelve years old, could not oppose Agrippina's power.

It wasn't long before it was believed that Britannicus, despite being only thirteen, could pose a threat. The reasons for what happened next are rather murky. For example, some claimed Agrippina, fearful of losing her influence over her son, wanted to replace him with her grandson, Caesarion. However, this theory seems unlikely in light of Agrippina's aforementioned—and alleged—machinations to bring her son—and consequently herself—to power. Likely influenced by Seneca or those close to him, Nero appears to have finally been convinced to rid himself of his half-brother to avoid potential problems.

In 55 AD, the young man was poisoned to death during a banquet attended by both Nero and the young Titus Flavius Vespasianus. Titus must have been close to the court, as his father, Vespasian, was one of the key imperial envoys during Claudius's British campaigns. Notably, the future emperor, a friend of both, apparently fell ill after accidentally ingesting some of the poison. As for the official story, Britannicus's death was passed off as an epileptic fit. This explanation, however, cannot be entirely ruled out, since the young man was said to have suffered from epilepsy since birth. Presumably, this condition also contributed to his exclusion from the succession. Finally, the conspiracy that Suetonius attributes to Nero could be shaped by the well-known hostility of the main sources toward the Julio-Claudian emperors, particularly Nero and his uncle Caligula.

Years later, during his brief reign, Titus honoured his friend by erecting several statues.