Methamphetamine use has been associated with HIV transmission among men who have sex with men (MSM). However, providers have been hesitant to utilize post-exposure prophylaxis (PEP) in populations of stimulant users. This single-arm, open label pilot study sought to demonstrate the safety, feasibility, and acceptability of PEP combined with the drug abstinence intervention of contingency management (CM) in methamphetamine-using MSM. HIV-uninfected MSM reporting recent methamphetamine use were recruited to a CM intervention. Those who reported a recent high-risk sexual or injection drug exposure to an HIV-infected or serostatus unknown source were initiated on tenofovir/emtricitabine (Truvada)-based PEP. Participants were followed over 3 months for infectious/biologic, behavioral, and drug use outcomes. Fifty-three participants enrolled in the study; 35 participants (66%) initiated PEP after a high-risk exposure. The median time from exposure to medication administration was 37.8 h (range 12.5-68.0 h). Twenty-five (71.4%) PEP initiators successfully completed the treatment course. Median medication adherence was 96% (IQR 57-100%), and medication was generally well tolerated. Methamphetamine abstinence during CM treatment increased PEP adherence (2% [95% CI +1-+3%]) per clean urine toxicology sample provided), and increased the odds of PEP course completion (OR 1.17, 95% CI 1.04-1.31). One incident of HIV seroconversion was observed in a participant who did not complete PEP treatment, and reported multiple subsequent exposures. Findings demonstrate that PEP, when combined with CM, is safe, feasible, and acceptable as an HIV prevention strategy in methamphetamine-using MSM.