The predecessor of SOM, the Western Pennsylvania Medical College opened its door to the first class of 57 students in 1886. The new college was erected on the lot between the Jones Avenue (today Brereton Street) and 30th Street in Polish Hill district. It was advertised as the state-of-the art facility with modern heating and ventilation system, spacious lecture rooms, labs, and the presence of Albert G. Walter Museum – a superb collection of several hundred specimens of deformities and calculi gathered by Dr. Walter and donated to the school by his wife.

The Western Pennsylvania Medical College merged with the Western University of Pennsylvania (predecessor of the University of Pittsburgh) as Medical Department in 1892. Within five years, the needs of the growing school necessitated an expansion. The new addition, which doubled the capacity of the school, was built next to the original building in 1897. On the adjacent lot the Emma Kaufmann Clinic was erected and both buildings were dedicated on March 24, 1897. The upgraded college building with two amphitheaters, multiple lecture rooms and new lab space opened for classes in 1898, and thus the medical students at the end of the 19th-century were starting their school year in the new and updated facility like those starting the school today.