Aims: Alcohol and illicit substance use among young adults carries the risk of adverse consequences like violence, injuries, risky sexual behaviour and, ultimately, the development of possible addiction. The nightlife arena is a high-risk setting for excessive substance use and the aims of this study were to examine prevalence rates and identify high-risk subgroups in this context. Methods: Patrons (n = 1099, response rate 76%) entering or exiting 12 popular licensed premises in downtown Oslo, Norway, completed an anonymous self-administered questionnaire and their blood alcohol concentration (BAC) levels were measured using a Breathalyzer. Results: The average BAC levels were similar (t = 1.67, degrees of freedom (df)= 936, non-significant (ns)) and high both for males (1.03) and females (0.97). A total of 67% reported ever using illicit drugs, 43% reported last-year use, 25% last-month use and 14% use during the last 48 hours. High-risk groups included the youngest patrons (16–20 years) where 50% reported illicit drug use in the last year. Males reported more use of illicit drugs than females, whereas females had equally high alcohol consumption frequency and intoxication levels as males. Young age, male gender, frequent alcohol intoxications and age < 15 for first alcohol intoxication experience were associated with increased risk of illegal substance use in multivariate analyses. Conclusions: The high levels of alcohol and illicit drug use, particularly among patrons younger than 21 years, should be of concern to the community, policymakers and the nightlife industry. The nightlife arena may be an under-utilized setting for the implementation of risk-reducing interventions.