Men who have sex with men (MSM) misuse prescription drugs at high rates. Little research has examined the connection between prescription drug misuse and HIV risk in this population. With a community sample of MSM, the authors assessed prescription drug misuse-not including erectile dysfunction medications-and sexual risk behaviors among HIV-negative MSM. The findings indicate that recent prescription drug misusers had higher odds of engaging in unprotected anal intercourse (UAI; OR = 1.63), specifically receptive UAI (OR = 1.58), and more likely to have UAI with a higher number of seroconcordant partners (b = 0.268). MSM who reported recently misusing prescription drugs during sexual encounters were more likely to engage in UAI (OR = 2.02), specifically insertive UAI (OR = 1.86). There was no association between prescription drug misuse and identification as a barebacker. This research indicates that prescription drug misusing MSM are a risk group who may benefit from HIV prevention and intervention efforts.