Background: Poverty, family stability, and social policies influence the ability of adolescents to attend school. Likewise, being enrolled in school may shape an adolescent’s risk for HIV and pregnancy. We identified trends in school enrollment, factors predicting school enrollment (antecedents), and health risks associated with staying in or leaving school (consequences). Methods: Data from the Rakai Community Cohort Study (RCCS) were examined for adolescents 15–19 years (n = 21,735 person-rounds) from 1994 to 2013. Trends, antecedents, and consequences were assessed using logistic and linear regression with robust variance estimation. Qualitative data were used to explore school leaving among HIV+ and HIV− youths (15–24 years). Results: School enrollment and socioeconomic status (SES) rose steadily from 1994 to 2013 among adolescents; orphanhood declined after availability of antiretroviral therapy. Antecedent factors associated with school enrollment included age, SES, orphanhood, marriage, family size, and the percent of family members <20 years. In qualitative interviews, youths reported lack of money, death of parents, and pregnancy as primary reasons for school dropout. Among adolescents, consequences associated with school enrollment included lower HIV prevalence, prevalence of sexual experience, and rates of alcohol use and increases in consistent condom use. Young women in school were more likely to report use of modern contraception and never being pregnant. Young men in school reported fewer recent sexual partners and lower rates of sexual concurrency. Conclusions: Rising SES and declining orphanhood were associated with rising school enrollment in Rakai. Increasing school enrollment was associated with declining risk for HIV and pregnancy.