Abstract. Aims: In this article we explore the moderators of effectiveness of WISEteens (Web-based brief Intervention for SubstancE using teens), a fully automated web-based brief motivational intervention targeting risky substance use among adolescents. Based on previous studies, we examined the differential effects on drinking of sex, readiness to change, self-efficacy, alcohol risk status, and parental monitoring as hypothesized moderators. Methods: We analyzed completers data from a two-armed RCT study with follow-up assessment after 3 months, including N = 211 self-enrolled adolescents (16 – 18 years) who screened positive for at-risk substance use in Sweden, Belgium, the Czech Republic, and Germany. The trial compared a single-session brief motivational intervention to an assessment-only control group with AUDIT-C scores for drinking frequency, quantity, and frequency of binge drinking in the past month as study outcome. Results: The analyses revealed a statistically significant moderation effect for sex on drinking in the previous month, with a stronger effect for males. In contrast, readiness to change, self-efficacy, alcohol risk status, and parental monitoring did not moderate the effects. Conclusions: Although the trial was limited by large dropout, our findings imply that web-based interventions can be particularly effective for male adolescents, although the effects of WISEteens were largely independent of other individual characteristics. Web-based brief intervention should integrate gender-specific components to raise effectiveness for females.