The 21-year-old Handel arrived in Italy in the fall of 1706. Although documentation on the early part of his tour is scarce, it is safe to assume that his first port of call was Florence, where he had been invited by Prince Ferdinando de'Medici. It was there that his first Italian opera, Rodrigo, was produced in November. Following its successful production, Handel appears to have spent the following winter in Venice, where he made the acquaintance of Domenico Scarlatti and probably met Cardinal Vincenzo Grimani. It was Grimani, a learned churchman and diplomat, who, two years later, would write the libretto of Handel's Venetian opera Agrippina. This was one of the finest libretti Handel would set. Unlike the sources of many operas of the period, which favored mythological stories, Agrippina is based on history.

The story is set in the Rome of the young Nero, and the plot is centered around the machinations of his mother Agrippina to get him on the imperial throne. Other principal characters are the Emperor Claudius, Agrippina's husband Otho, the emperor's lieutenant, and his beloved, the flirtatious Poppea, who is also desired by both Claudius and Nero. From this story, Grimani fashioned a typically Venetian libretto in which intrigue, witty observations, and a certain black humor prevail. However, avoiding the amoral conclusion of Monteverdi's L'incoronazione di Poppea, composed in Venice some 70 years earlier, Grimani's libretto does not allow all the evil schemes to triumph. In keeping with the tenets of earlier Venetian opera, which had not yet been confined to the straitjacket of opera seria form, there is a flexibility in Agrippina rarely encountered in Handel's later London operas. In addition to the expected da capo arias, there are a number of ariettas, ariosos, and cavatinas, as well as a quartet, a trio, and a couple of choruses, the last rarely found in opera seria. This work is typical of the fresh, exuberantly inventive music Handel composed during his Italian years, a period during which he first became feted as a celebrity. The exact date of the first performance of Agrippina at the Teatro San Giovanni Gristostomo, which was owned by the librettist Grimani, is not known, but a likely time is early January 1710, just after the start of the Carnival season. The production was a tremendous success for Handel, who, according to his earliest biographer Mainwaring, was greeted with continual cries of "Vivo il caro Sassone" (Long live the dear Saxon). Subsequently, the opera was repeated on 26 successive nights, an astonishing feat at this time, and one made all the more remarkable by the fact that operas by two of the leading Venetian composers of the day, Gasparini and Lotti, were concurrently playing in other opera houses in the city.

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