This study examined whether there are subgroups of families with distinct profiles of prenatal/birth contextual risk, and whether subgroup membership was differentially related to adolescent substance use. Data from the Northern Finland Birth Cohort 1986 were used. A five-class model provided the most meaningful solution. Large Family Size (7.72%) and Low Risk (69.69%) groups had the lowest levels of alcohol, cigarette, and illegal drug use. Similar high levels for each of the three substance-related outcomes were found for Parent Substance Misuse (11.20%), Maternal School Dropout (4.66%), and Socioeconomic Disadvantage (6.72%) groups. Maternal smoking and drinking while pregnant and paternal heavy alcohol use were found to be key prenatal risk factors that tended to cluster together and co-occur with other prenatal risk factors differently for different subgroups of youth.