Abstract: Objective To understand the awareness level of AIDS knowledge and its influencing factors among middle school students from AIDS high prevalence areas of Yi Autonomous Prefecture (Liangshan Prefecture), and to provide a reference for making propaganda strategies of AIDS knowledge and intervention measures in the relevant departments. Methods Totally 10 749 students in 4 middle schools were selected from AIDS high prevalence areas of Yi Autonomous Prefecture in Liangshan by the method of cluster sampling. A self-made questionnaire was used to investigate the ways of getting AIDS knowledge and the condition of conducting AIDS life training skills in school. Results The awareness rate of AIDS-related knowledge among middle school students in Liangshan Prefecture was 44.4%. According to the results of multivariate Logistic regression analysis, female students, junior grade, Yi nationality, poor self-evaluation, lack of parents, living in rural areas, good family economic condition (student self-assessment), living in a community of Yi nationality were all the dangerous factors to the awareness rate of AIDS. School education, radio and television, and health promotion were the main ways for students to acquire AIDS knowledge (88.82%, 80.83%, 73.54%). Minority students, students in severely affected areas received less AIDS life skills training in schools, the time was later, and student needs were not strong. Conclusion The AIDS awareness level of middle school students in Liangshan AIDS high-incidence area is too low, so it is necessary to pay attention to develop targeted programs to strengthen AIDS health education for middle school students.