Fortune's Favorites continues the saga of the Gaius Marius-Sulla-Caesar-Pompey line of Roman rulers begun in The First Man in Rome. Fortune's Favorites differs in that, as McCullough states in an afterword to the novel, it begins the process of providing less of the broad sweep of the history of Mediterranean civilization, and begins to focus more on Rome and the fall of its republic.

The epistolary techniques are still in the novel, but are fewer than in The First Man in Rome — Publius Rufus is both a more frequent and more literate correspondent than Pompey, whose few missives are blunt and to the point and rhetorically inept.