Aims: We describe types of polydrug use among school students across Europe and explore differences between high, medium and low drug prevalence countries. Method: Analysis is based on survey data from over 70,000 15- to 16-year-old school students in 22 European countries. Polydrug use (defined as the use of two or more listed substances during the last 30 days) is compared across three country clusters based on drug prevalences by hierarchical cluster analysis. Affinity between substances is measured by pairwise associations and regression analysis was used to assess the differences in rate ratio across the country clusters. Results: A third of all school students had consumed two or more substances. The most common combinations were: alcohol and cigarettes, followed by alcohol or cigarettes combined with cannabis, followed by alcohol or cigarettes, cannabis and at least one other illegal drug. Pairwise associations show that cannabis and cocaine users are more likely to use illegal drugs than the general student populations but least likely to do so in countries with high prevalence levels (p less than 0.0005). Conclusion: Consideration of country differences and objective measures for the concept of normalization could help to inform more holistic prevention initiatives that respond to country-specific contexts. (Contains 10 notes, 3 tables, and 2 figures.)