We determined whether methamphetamine use is associated with the increased prevalence of primary HIV drug resistance among a cohort of men who have sex with men recently infected with HIV. In multivariate analysis, we found that frequent methamphetamine use was strongly associated with primary non-nucleoside reverse transcriptase inhibitor resistance, but not with protease inhibitor or nucleoside reverse transcriptase inhibitor resistance. We postulate that this association may be caused by methamphetamine-associated treatment interruptions among source partners.