Background: Although males are often the initiators of teen sexual activity, pregnancy prevention programs generally target females. To address this deficiency, the Wise Guys Male Responsibility Curriculum was developed to be delivered to adolescent males in weekly classroom sessions. Methods: Seventh grade participants (n = 124) in the Wise Guys program were compared to randomly selected controls (n = 106) at pretest (baseline), posttest, and 6-month follow-up data points. Comparisons were made on knowledge of sexual behavior and reproductive biology, knowledge of sexually transmitted disease (STD) transmission, desirable attitudes toward sex and appropriate behavior in sexual relationships; and on limited behavioral outcomes, including initiation of sexual activity, and use of condoms and contraception by sexually active adolescents. Results: Wise Guys participants demonstrated greater posttest and follow-up knowledge of sex and reproductive biology (p less than 0.000), greater knowledge of STD transmission (p less than 0.000), and higher rates of desirable attitudes toward sex and appropriate behavior in sexual relationships (p [less than or equal to] 0.013) than controls. Favorable behavioral changes were also reported among sexually active participants at follow-up. Conclusions: The Wise Guys curriculum effectively improves adolescent males' knowledge of sexual behavior and reproductive behavior, and their knowledge of STD transmission, and instills desirable attitudes toward sex and appropriate behavior in sexual relationships. The results also indicate that the curriculum may promote greater condom use and contraception among sexually active males. (Contains 5 tables.)