Introduction: This cross sectional study was conducted to explore the moderating effect of sexual sensation seeking (SSS) on the association between alcohol/popper use before sex and multiple sexual partners (MSP) among men who have sex with men (MSM) in Guangzhou, China. Methods: From June 2017 to April 2018, MSM were recruited from a community-based HIV service center in Guangzhou, China; data on sociodemographics, sexual behaviors and SSS were collected. A product term of SSS and alcohol/popper use before sex was included in a multivariate logistic regression model to test the potential moderating effect of SSS on the association between alcohol/popper use before sex and MSP. Results: Among the 500 MSM included, individuals who reported alcohol use and popper use before sex, and MSP in the last six months accounted for 33.80%, 33.40%, and 60.40%, respectively. MSM with high SSS traits accounted for 54.80%. The association between popper use before sex and MSP was moderated by SSS (P for interaction = 0.007). A significant association between popper use before sex and MSP among MSM with low SSS traits (odds ratio [OR] = 4.22, 95% confidence interval [CI]: 2.06 ∼ 8.67). But not among MSM with high SSS traits (OR = 1.37, 95%CI: 0.77 ∼ 2.43) were observed. However, no moderating effect of SSS on the association between alcohol use before sex and MSP were observed. Conclusion: The moderated analysis indicated that SSS should be taken into consideration when tailoring interventions to prevent popper use before sex to reduce the risk associated with MSP. [ABSTRACT FROM AUTHOR]