The famous Annunciation (1533 - 1535), one of the Master's absolute masterpieces, was created for the Confraternity of the Merchants of Recanati. The representation of the religious event of the Annunciation is very frequent in the history of art but in this case the connotation attributed to it by Lorenzo Lotto is certainly new and particular, if not revolutionary. The reasons that make this Annunciation unique compared to all the others are essentially two: the singular attitude of the Virgin, who instead of being turned towards the Angel, as per tradition, looks frightened at the viewer seeking almost comfort and consolation, and the presence of a cat, at the center of the scene, a symbol of evil but at the same time also an ironic and ambiguous element, which runs away in fear in the face of the arrival of the Angel sent by God the Father. Noteworthy is the description of the details of the room, clearly of Nordic inspiration.

The majestic Polyptych of San Domenico, completed in 1508, was commissioned by the Dominican Fathers and also built thanks to the financial contribution of the Municipality of Recanati and the Confraternity of Santa Lucia. The painting presents a traditional architecture where the artist inserts monumental and restless figures, immersed in a penumbra crossed by a light that creates strong contrasts. The altarpiece hides a profound meaning and was born as a work of protest against a serious injustice against the city of Recanati, from which Julius II removes jurisdiction over the Sanctuary of Loreto, built to house the Holy House of Nazareth which reached the territory Recanatese in 1294. The work closes the youth cycle of Lotto's activity, now a mature painter aware of his own means.

The San Giacomo Maggiore, from 1512 - 1513, is a precious miniature dominated by the imposing figure of the Saint, with a lost and melancholy gaze. San Giacomo is a sad and weary traveler and recalls the figure of the artist in his restless and pilgrim being, so much so that several art historians have ventured the hypothesis that the work is actually a self-portrait of the same artist.

The Transfiguration, dating back to around 1511 and commissioned to the artist by the Confraternity of the Ancient Church of Santa Maria in Castelnuovo, reveals Raphaelesque influences; landscape and figures are represented with pathetic impulses and very deep expressive motions, the apostles flatten themselves on the ground, in total absence of perspective and its rules, and cover their faces dazzled by the Transfiguration of Christ, highlighting all the distance that it separates Christ and the Prophets Moses and Elijah, who are above them, from the otherworldly world. The work is rich in theological and spiritual meanings and Lotto seems to be almost no longer the same artist who created the Polyptych of San Domenico, the influence of Raphael is evident, however, it is translated into a new identity.