Betances returned to Puerto Rico in April 1856. At the time, a cholera epidemic was spreading across the island. The epidemic made its way to Puerto Rico's western coast in July 1856, and hit the city of Mayagüez particularly hard. At the time, Betances was one of five doctors that would have to take care of 24,000 residents. Both he and Dr. José Francisco Basora (who became lifelong friends and colleagues from that point on) would alert the city government and press the city managers into taking preventive action.