Consistent with cumulative risk hypotheses of psychopathology, studies examining prenatal adversity and later mental health largely suggest that pre and postnatal stress exposures have summative effects. Fewer data support that a mismatch in stress levels between pre- and postnatal life increases risk (the mismatch hypothesis). In this retrospective cohort study using data from the 1983 Ontario Child Health Study (OCHS), we examined interactions between birth weight status and childhood/adolescent stress to predict major depression in adulthood. Ninety-five participants born at low birth weight (LBW; <2500 g) and 972 normal birth weight (NBW) control participants completed the Composite International Diagnostic Interview Short-Form Major Depression module at 21–34 years of age. A youth risk scale consisting of five stressful exposures (family dysfunction, socioeconomic disadvantage, parental criminality, maternal mental illness, exposure to other life stresses) indexed child/adolescent adversity. Birth weight groups did not differ by childhood risk score nor depression levels. A significant interaction was observed between birth weight and the youth risk scale whereby exposure to increasing levels of exposure to childhood/adolescent adversity predicted increased levels of depression in the NBW group, but lower rates in those born at LBW. Consistent with the mismatch hypothesis, data from a large, longitudinally followed cohort suggest that the mental health of adults born LBW may be more resilient to the adverse effects of childhood/adolescent stress. Taken in the context of previous studies of low birth weight infants, these findings suggest that the nature of associations between gestational stress and later mental health may depend on the magnitude of prenatal stress exposure, as well as the degree of resilience and/or plasticity conferred by their early-life environment.