Secular trends in nonoccupational postexposure prophylaxis (NPEP) use have not been well characterized. We performed a retrospective longitudinal study of 894 electronic medical records of NPEP users, mostly men who have sex with men, at a Boston community health center who presented between July 1997 and August 2013. NPEP use and condomless sexual exposures increased over time; 19.4% had multiple NPEP courses. Having an HIV-infected partner was associated with increased odds of regimen completion, and 3-drug regimens were associated with decreased odds of completion. Targeted adherence and risk-reduction counseling are warranted for select NPEP users at this center.