This study evaluates the efficacy of Keepin' It Safe, a theory-based, gender-specific, CD-ROM-mediated HIV prevention program for urban, early adolescent girls. Intervention effects were examined in a randomized, pretest-posttest wait-list control-group design. Changes in HIV/AIDS knowledge, protective attitudes, and skills for reducing HIV risk-related sexual behaviors were tested using linear regression models that were controlled for baseline values of each outcome. Recruited through youth services agencies located in the greater New York City area, study participants comprised 204 adolescent girls aged 11-14 years. Girls exposed to Keepin' It Safe, relative to wait-list control girls, increased their HIV/AIDS knowledge, perceived efficacy and enjoyment of abstinence, perceived efficacy and enjoyment of condoms, and sexual assertiveness, suggesting that a theory-based, gender-specific, CD-ROM-mediated HIV prevention program can enhance knowledge, protective attitudes, and skills for reducing HIV risk-related sexual behaviors among urban early-adolescent girls.