The church lies on the site of a primitive worship place erected by the archbishop Anspertus in 879, dedicated to Saint Satyrus, confessor and brother of Saints Ambrose and Marcellina. The current church was instead built from 1472 to 1482 under commission from Duke Galeazzo Maria Sforza. According to some sources, the designer was Bramante, who had recently moved from the Marche. However, recent documents prove that Bramante had a minor role, most of the work being attributable to Giovanni Antonio Amadeo, who designed the façade. Certainly from Bramante is the sacristy perspective.
The edifice has a nave and two aisles with barrel vault. The nave is surmounted by an emispherical dome at the crossing with the transept. The choir, which had to be truncated due to the presence of a main road, was replaced by Bramante with a painted perspective, realizing in this way one of first examples of trompe l'oeil in history of art.
Originally the interior was decorated with white and gold paint. The walls had frescoes by Borgognone, now transferred to the Pinacoteca di Brera. The ancient sacellum of San Satiro was also covered with cotto decoration and enriched with a terracotta portraying the Dead Christ by Agostino de Fondulis. Also by the same artist are several terracotta busts in the sacristy, which is on the central plan, inspired to the Portinari Chapel of Sant'Eustorgio or to the Colleoni Chapel.
The bell tower is still that of the Romanesque edifice preceding the 1480s reconstruction. Also from the 15th century is the baptistry annexed to the church.
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