The purposes of this study were to identify whether there are gender differences in sexual behaviors among Korean adolescents and to explore the factors that influence safe sex practices across both sexes. A secondary analysis was conducted using nationally representative data obtained from the 2014 Youth Risk Behavior Web-based Survey. Sample consisted of 3,210 adolescents who had experience of sexual intercourse. The dependent variable in this study was practicing safe sex. The independent variables included a range of individual, family, and school factors. Female adolescents were less likely to practice safe sex (i.e., always using a condom). Individual (smoking, no drinking before sexual intercourse), family (living with parents, higher allowance per week) and school factors (non-coeducational school students, had received school-based sex education) were significant predictors of practicing safe sex in males. In contrast, family (lower economic status) and school factors (middle school students) predicted practicing safe sex among female adolescents. We demonstrated that gender plays an important role in the sexual behavior of adolescents. The findings of this study indicate a need to design and implement gender-specific interventions. •Our study indicated that a higher reporting of unhealthy lifestyle (i.e., drinking alcohol and smoking) in males compared to that in females•We found that female adolescents reported less responsible safe sexual behavior than male adolescents in Korea•Efficient strategies for improving knowledge regarding sexuality and access to contraceptive use should be initiated at the national level•Gender-specific reproductive and sexual health education should focus on enhancing the use of safe sexual practices for female adolescents•For males, education focusing on modifiable health behaviors such as abstaining from alcohol and cigarette use could be beneficial