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The study objectives were to determine the effects of a large- scale school-based HIV prevention campaign, in terms of both positive and negative effects of each single message, and to identify sub- populations more at risk. Forty-six schools, randomly sampled from all schools in the Lazio region, were randomized to either an intervention or a control group. The study population consisted of 3866 students. Questionnaires on AIDS-related knowledge and risk perceptions were administered to students before and after the intervention. Odds ratios were calculated to represent the extent to which the intervention was associated with an improvement (OR+), and the extent to which it prevented a worsening (OR−). Overall, the intervention was successful in communicating important messages, such as the impossibility of transmitting HIV through social contacts (OR+ all significantly >1 and OR− always 1 were observed for only three questions and OR− values usually exceeded 1. This study highlights the necessity of remodelling the intervention, indicating which messages need to be modified. The low impact of educational programmes among students of vocational and art schools makes them a population more at risk, that should be considered as a priority target population for interventions.