Background: Adolescent girls and young women (AGYW) remain burdened by the HIV epidemic. Positive caregiver-child relationships are associated with safe sexual behaviors in young people; yet, this literature often highlights the role of parent-child communication and parental monitoring, neglecting the importance of emotional relationships between a caregiver and adolescent. Setting: We used longitudinal data from HIV Prevention Trial Network 068-conducted among 2533 AGYW (13-20 years) over a period of 5 years in Agincourt, South Africa. Method: Kaplan-Meier and Cox models were used to estimate the effect of quality of caregiver-adolescent relationships (caring and closeness) on sexual debut, and log-binomial models with generalized estimating equations were used to examine the relationship between our exposures and transactional sex and age-disparate relationships. Results: Sexual debut was delayed among those who reported high levels of caregiver caring [hazard ratio: 0.80, 95% confidence interval (CI): 0.69 to 0.93] and caregiver closeness (hazard ratio: 0.80, 95% CI: 0.68 to 0.95). AGYW who reported high quality caregiver-adolescent relationships had a lower risk of transactional sex [caring: risk ratio (RR): 0.67, 95% CI: 0.58 to 0.78; closeness: RR: 0.58; 95% CI: 0.50 to 0.67]. Similarly, those with high-quality caregiver-adolescent relationships were less likely to be in an age-disparate relationship (caring: RR: 0.68, 95% CI: 0.58 to 0.79; closeness: RR: 0.77, 95% CI: 0.66 to 0.90). Conclusions: Findings indicate high-quality caregiver-adolescent relationships are associated with delayed sexual debut, a lower risk of transactional sex, and having an older partner. Family-centered interventions are needed to improve relationships between AGYW and caregivers.