Shakespeare's next major encounter with Rome, Antony and Cleopatra, is in many ways a sequel to Julius Caesar. Antony's fatal infatuation with Cleopatra commanded as much attention in the Renaissance as did Caesar's assassination. In M. W. MacCallum's words:

In addition to the popularity of subject matter, the two plays share a focus on the same critical juncture in Roman history: the decades encompassing the dissolution of Republic and the birth of Empire. Both plays derive from Plutarch's Lives; both freely incorporate material from other writers, notably Appian and Vergil; both express Shakespeare's increasingly critical conception of Rome and Roman values. Like Julius Caesar and Shakespeare's other Roman works, Antony and Cleopatra examines the struggle of Romans with Rome, portrayed as a physical locality and an imagined ideal. The play explores the resulting conflict between private needs and public responsibilities by again focusing on the Roman code of honor, shame, and fame; the paradoxes implicit in Roman ceremony and ritual; the political motifs of rebellion and invasion. As do Shakespeare's previous Roman works, Antony and Cleopatra explores the predicament of the living human beings who must define themselves against the oppressive background of Roman tradition and history.