BACKGROUND: The rate of HIV/AIDS infection is increasing every year. The highest rates of HIV infection are among adolescents aged 15–24 years. Therefore, appropriate action is needed to prevent HIV transmission through risky behavior in adolescents. AIM: The purpose of this study was to determine the effect of Kasaba Quartet card game on HIV/AIDS knowledge and self-efficacy in preventing HIV/AIDS-related risk behavior in adolescents. METHODS: The study used a quasi-experiment with an equivalent time-series design. The intervention in this study was a card game using the Kasaba Quartet. The card game was held 3 times with a 1-day break. Adolescents’ HIV/AIDS knowledge and self-efficacy were measured at the end of each card game. Sampling used purposive sampling with criteria including adolescents aged 12–16 years and domiciled in Bandung. A total of 30 people were involved in this study. RESULTS: After playing the Kasaba Quartet card game, the results showed that adolescents’ knowledge of HIV/AIDS in the excellent category increased significantly, with average scores from 66.04 ± 16.219 to 97.40 ± 2.776. Likewise, adolescents’ self-efficacy with the high sort was raised, from 77.83 ± 8.67 to 97.60 ± 3.45. The results of statistical tests using the Friedman test showed the significance level of 0.001 (Sig. <0.05). In other words, there was an effect of the Kasaba quartet card game on HIV knowledge and self-efficacy in preventing HIV risk behavior. CONCLUSIONS: Thus, the Kasaba Quartet card game effectively increases knowledge of HIV/AIDS and self-efficacy in preventing risky behavior in adolescents. The study results can be used as an alternative strategy to increase knowledge and confidence in adolescents to avoid the spread of HIV/AIDS cases.