Summary Antwerp’s response to the outbreak of plague in the 1570s offers new insights into the effects of epidemics on urban communities in relation to their religious, economic, and spatial fabric. Antwerp’s transition from a Catholic to Calvinist government in 1577, and back to Catholicism in 1585, allows us to study its reaction to and the effects of plague across religious boundaries within a short time span. Using GIS, we have compared various rich datasets concerning plague: the register of houses locked in quarantine; the health certificates issued by authorities; plague fatalities recorded in St. Jacob’s parish; a wide range of urban regulations; and information about the size of households, their composition, rents and real estate values in Antwerp. Combined analysis shows that Catholics and Protestants, whose houses were concentrated in different city districts and who had distinct professional and economic profiles, experienced plague quite differently, both physically and spiritually.