AbstractIntroduction and AimsParticipation in nightlife influences a range of health behaviours. Participants in various nightlife scenes have increasingly adopted prescription drug misuse into their substance use repertoires.Design and MethodsWith 404 young adults recruited via time–space sampling in New York, we examine the relationship of nightlife participation—measured by number of scenes and the number of nights out in nightlife scenes—to prescription drug misuse during the past 3 months. Outcomes included frequency of misuse, escalation to non‐oral consumption, polydrug use, social problems and symptoms of dependence.ResultsNegative binomial regressions indicate nightlife participation is associated with increased frequency of misuse measured by number of scenes (incidence rate ratio = 1.114, P < 0.05) and number of nights out (incidence rate ratio = 1.009, P < 0.001). Logistic regression models show nightlife participation is associated with increased odds of non‐oral use (adjusted odds ratio; AOR = 1.334, P < 0.01) and polydrug use (AOR = 1.776, P < 0.001) measured by number of scenes, and non‐oral use (AOR = 1.021, P < 0.001) and polydrug use (AOR = 1.023, P < 0.001) as measured by number of nights out. Nightlife participation is not associated with prescription drug problems or symptoms of dependence. Frequency of participation is associated with peer norms favourable to prescription drugs (B = 0.003, P < 0.01).Discussion and ConclusionsNightlife participation has implications for prescription drug misuse. While shaping how often and in what manner young people consume prescription drugs, nightlife participation is not associated with harms experienced. Given the significance of the prescription drug trend in many world regions, these results suggest that increasing participation in nightlife shapes patterns of drug use, but in ways that do not lead to reported problems.