Abstract: Objective To investigate drug knowledge of middle school students in HIV prone areas in Liangshan of Sichuan Province. Methods Students were randomly selected from the middle schools located in the HIV prone areas in Liangshan. A questionnaire survey was conducted. Drug knowledge of the respondents and associated factors were analyzed. Results Of the 10 749 respondents, 10.1% had wrong knowledge about drugs. The respondents of male gender and minority ethnicity in the region and those who were in a lower grade, had poor academic records, more sisters, and a schoolmate taking drugs, and lived in a family with HIV infected member were more likely to had poor drug knowledge. By contrast, the respondents who had a peasant father, lived with both parents, resided in a city or township, self-rated in the middle and low 1/3 of wealth, lived in a community with >50% school attendance, and had a family member taking drugs were less likely to have wrong drug knowledge. Conclusion Middle school students in the HIV prone areas in Liangshan have poor drug knowledge. Socioeconomic factors influence the drug knowledge of students, which require systematic interventions.