Background: There is relevant scientific evidence supporting the need to invest in preventing the use of psychoactive substances in higher education, particularly amongst first-year university students.Goals: The purpose of this research was to assess the effectiveness of an original prevention program, the Risks & Challenges, in reducing psychoactive substance use and its negative consequences, as well as to assess its effectiveness in reducing the exposure to risk factors and enhancing the effect of protection factors related to addictive behaviors among university students.Methods: This is a community based open-label controlled trial. The sample consisted of first-year students from the University of Minho, in Portugal, who voluntarily enrolled in the Risks & Challenges Program. Data were collected at baseline, post-intervention and at a 6-months follow-up. Students were randomly assigned to intervention and control groups. In addition to collecting sociodemographic and psychoactive substance-use data, the following instruments were self-administered: AUDIT, Self-Control Scale, Sensation Seeking Scale Version V, Academic Experience Questionnaire, Rosenberg Global Self-esteem Scale and Beck Depression Inventory. Results: The study involved 228 students. Students allocated to the intervention group (n = 98) reported a significant reduction in alcohol consumption as well as in the expectations for cannabis and alcohol use. Furthermore, the intervened students improved in personal and interpersonal dimensions of academic experiences and in self-esteem, with significant decrease of depression, anger and tension indicators. Discussion: These findings support the conclusion that the Risks & Challenges Program can be a valuable tool for preventing drug use in first-year university students. Significant preventive effects were found, reinforcing the relevance of using this program among higher-education students. Keywords: Prevention, Addiction, Risk behavior, Effectiveness evaluation, Adolescents.