OBJECTIVES: This study examined the association between sexual and reproductive health (SRH) education in peer-group discussion and comprehensive knowledge of HIV among young adolescent girls in rural eastern Ethiopia. DESIGN: The study analysed data from a large quasi-experimental study involving 3290 young adolescent girls aged 13-17 years. The intervention targeted adolescent girls aged 10-14 years. Data were collected using a comprehensive HIV knowledge tool adopted from the demographic and health survey questionnaire. Multi-level mixed-effect logistic regression analysis was employed to examine associations using STATA/SE V.14 statistical software. SETTING: West Hararghe, rural Ethiopia. PARTICIPANTS: 3290 adolescent girls. RESULTS: Magnitude of comprehensive knowledge of HIV among those who received SRH education and those who did not receive SRH education was 16.78% (95% CI 14.41% to 19.45%) and 14.01% (95% CI 12.38% to 15.81%), respectively. Overall, 14.84% (95% CI 13.4.% to 16.39%) of the adolescent girls aged 13-17 years had comprehensive knowledge of HIV. The odds of having comprehensive HIV knowledge were higher (1.36 times) among adolescent girls who received SRH education compared with those who did not receive SRH education (adjusted OR 1.36, 95% CI 1.01 to 1.84) after controlling for selected potential confounders. Odds of having comprehensive HIV knowledge were also higher (1.73 times) among older adolescent girls (adjusted OR 1.733 95% CI 1.098 to 2.735) and (3.89 times) among those who attended secondary school (adjusted OR=3.889 95% CI 1.836 to 8.235) compared with young adolescent girls and the uneducated, respectively. CONCLUSIONS: Comprehensive knowledge of HIV among young adolescent girls was very low. Providing SRH education for young adolescent girls improved their comprehensive knowledge of HIV in rural eastern Ethiopia. Initiating sexual education at an early age would benefit HIV prevention efforts.