Brief interventions (BI) commonly employ screening and target a single substance. Multi-substance interventions are a more adequate reflection of risk behaviors in adolescents and young adults. Systematic screening complicates BI in many settings. The effectiveness of a voluntary multi-substance intervention among 19-year-old men and the incremental impact of booster sessions were analyzed. Participants were enrolled during mandatory army conscription in Switzerland. Compared with 461 controls, 392 BI subjects showed reduced substance use on 10 of 12 measures (4 tobacco, 4 cannabis, and 2 alcohol measures). Between-group effects were small and non-significant (except for cannabis use prevalence). Three-month booster sessions were not effective and even contraindicated. The usefulness of targeting multi-substances during BIs without prior screening depends on the value of small effects. The addition of booster sessions was not effective and therefore is not recommended.