ABSTRACT: Increasing evidence suggests an association between synthetic drug use and HIV infection among men who have sex with men (MSM). The aim of this study was to evaluate synthetic drug use prevalence, describe characteristics of synthetic drug users, and investigate whether synthetic drug use is associated with HIV infection among Chinese MSM.A cross-sectional survey was conducted in 16 Chinese cities among males >18 years old who reported having had sex with men in the prior 3 months, but did not already have a known HIV-positive serostatus. Participants were grouped according to lifetime synthetic drug use and characteristics were compared using Chi-square test. Determinants of HIV infection were assessed using univariate and multivariate regression.Among 3,135 participants, 1,249 reported lifetime synthetic drug use, for a prevalence of 39.8%. Nearly all users (96.3%) reported using inhaled alkyl nitrites ("poppers"). Synthetic drug users were more likely to be younger (<30 years, p<0.001), single (p<0.001), and more educated (p<0.001), and were more likely to engage in higher risk sexual behavior compared to non-drug users. Overall HIV prevalence was 7.8% (246/3,135). However, prevalence among synthetic drug users was 10.6% (132/246) compared to 6.0% (114/246) for non-drug users (p<0.001). Factors associated with an increased odds of HIV infection included inconsistent condom use with male partners (adjusted odds ratio [OR] = 2.18, 95% confidence interval [CI] = 1.64-2.91) and synthetic drug use (adjusted OR = 2.04, CI = 1.56-2.70).Prevalence of synthetic drug use, especially poppers use, prevalence was high in our study, and users had 2-fold greater odds of HIV acquisition. It is clear that there is an urgent need for increased prevention, testing, and treatment interventions for this key, dual-risk population in China. Moreover, we call on the Chinese Government to consider regulating poppers so that users can be properly warned about their associated risks.