Nitrite inhalants (poppers) are commonly used recreational drugs among MSM and were previously associated with elevated rates of high-risk sexual behavior, HIV and human herpesvirus type 8 (HHV-8) seroconversion, and transient immunosuppressive effects in experimental models. Whether long-term popper use is associated with cancer risk among MSM in the HAART era is unclear. Prospective cohort study of cancer risk in 3223 HIV-infected and uninfected MSM in the Multicenter AIDS Cohort Study from 1996-2010. Poisson regression models were used to examine the association between heavy popper use (defined as daily or weekly use for at least 1 year) and risk of individual cancers or composite category of virus-associated cancers. Among all participants, heavy popper use was not associated with increased risk of any individual cancers. Among HIV-uninfected men aged 50-70, heavy popper use was associated with increased risk of virus-associated cancer with causes linked to human papillomavirus, HHV-8, and Epstein-Barr virus in models adjusted for demographics, number of sexual partners, immunological parameters (CD4 cell counts or CD4/CD8 ratios), and hepatitis B and C viruses [incidence rate ratio (IRR), 95% confidence interval (CI) 3.24, 1.05-9.96], or sexually transmitted infections (IRR 3.03, 95% CI, 1.01-9.09), as was cumulative use over a 5-year period (IRR 1.012, 95% CI 1.003-1.021; P = 0.007). There was no significant association between heavy popper use and virus-associated cancer in HIV-infected men. Long-term heavy popper use is associated with elevated risk of some virus-associated cancers with causes related to human papillomavirus, HHV-8, and Epstein-Barr virus infections in older HIV-uninfected MSM independent of sexual behavior and immunological parameters.