Substance use is increasing among youth in South Africa, and may be contributing to transmission of HIV. As parental death often leaves youth with altered emotional and physical resources, substance use may be greater among orphaned adolescents. Utilizing data from a household survey of 15-24 year old South Africans (n = 11,904), multivariable models were fitted to examine the association of factors from five domains with alcohol and drug use, and to compare substance use among orphaned versus non-orphaned youth. Results showed that factors from individual, family, and community domains were most associated with substance use. Compared with non-orphans, paternal and double orphaned males were more likely to have consumed alcohol, and paternally orphaned females had significantly greater odds of having used drugs. Findings confirm that some sub-groups of orphaned youth are at increased risk of substance use and families and communities may be influential in moderating this risky behavior. (Contains 4 tables and 2 figures.)