Methamphetamine use among participants in this study inverted the functional form of the relationship between depression and sexual risk among MSM observed in prior studies. Whereas low-grade depression has been associated with increased sexual risk-taking in prior samples of MSM, methamphetamine upends this relationship, such that the greatest engagement in sexual risk-taking occurred among those diagnosed with MDE at baseline. Additional research is warranted to clarify how methamphetamine influences sexual risk-taking among MSM with/without comorbid depression.