(1) Background: Condomless anal sex and substance use are associated with STI risk among gay, bisexual, and other men who have sex with men (gbMSM). Our first study objective was to describe event-level sexual risk and substance use trends among gbMSM. Our second study objective was to describe substances associated with event-level sexual risk. (2) Methods: Data come from the Momentum Health Study in Vancouver, British Columbia and participants were recruited from 2012-2015, with follow-up until 2018. Stratified by self-reported HIV status, we used generalized estimating equations to assess trends of sexual event-level substance use and assessed interactions between substance use and time period on event-level higher risk sex defined as condomless anal sex with an HIV serodifferent or unknown status partner. (3) Results: Event-level higher risk anal sex increased across the study period among HIV-negative/unknown (baseline prevalence: 13% vs. study end prevalence: 29%) and HIV-positive gbMSM (baseline prevalence: 16% vs. study end prevalence: 38%). Among HIV-negative/unknown gbMSM, event-level erectile drug use increased, while alcohol use decreased over the study period. Overall, interactions between substance use and time on higher risk anal sex were not statistically significant, regardless of serostatus. However, we found a number of time-specific significant interactions for erectile drugs, poppers, Gamma-hydroxybutyrate (GHB), crystal methamphetamine and ecstasy/MDMA use among HIV-negative/unknown gbMSM. (4) Conclusion: Significant differences in substance use trends and associated risks exist and are varied among gbMSM by serostatus. These findings provide a more comprehensive understanding of the effects of event-level substance use on sexual risk through longitudinal follow-up of nearly six years.