The purpose of this study was to explore the safe sex behavior and related factors of junior college students with sexual experience in southern Taiwan. This study used a cross-sectional design, in which data from a sample of 187 junior college students with sexual experience were collected by an anonymous and self-administered questionnaire. For a conceptual framework, the study used constructs from the PRECEDE (Predisposing, Reinforcing, and Enabling Causes in Educational Diagnosis and Evaluation) model. Two predisposing factors (AIDS-prevention self-efficacy, AIDS related knowledge), one enabling factor (school resources in AIDS prevention), one reinforcing factor (perception of peers' AIDS prevention behavior), demographic characteristics (gender, parents' educational level), substance use (cigarette and alcohol use) and sexual history (age of first sexual intercourse, number of sexual partners) were examined for their ability to influence safe sex behavior of junior college students with sexual experience. The results showed that gender, fathers' educational level, age of first sexual intercourse, number of sexual partners, cigarette use and alcohol use were significant factors for difference in safe sex behavior. AIDS prevention self-efficacy, AIDS-related knowledge, and perception of peers' AIDS prevention behavior were all positively related to safe sex behavior. AIDS prevention self-efficacy, fathers' educational level accounted for 49.8% of the variance in safe sex behavior.