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Background: Prenatal alcohol and tobacco exposures have been associated with adverse mental health consequences in offspring. The objective of this study was to test the associations between maternal prenatal alcohol and tobacco exposures and depressive symptoms in the offspring, adjusting for a wide range of potential confounders. Methods: We used data from 1168 mother-offspring pairs from the Raine Study based in Perth, Western Australia. Depressive symptoms at age 17 years were measured using the Beck Depression Inventory for Youth (BDI-Y). Associations between prenatal alcohol and tobacco use and the risk of depressive symptoms in offspring were estimated by risk ratios (RR) derived with multivariable log-binomial regression. Results: Among offspring who were assessed for depressive symptoms, 5% were born to mothers who consumed six or more standard drinks of alcohol per week during pregnancy and 20% were exposed to prenatal tobacco. After adjustment for confounders, depressive symptoms at the age of 17 years remained associated with maternal alcohol use of six or more standard drinks per week [RR 1.59 (95% CI: 1.11-2.26)] and any tobacco use [RR 1.36 (95% CI: 1.05-1.79)] during the first trimester of pregnancy. Conclusion: Offspring exposed to prenatal alcohol and tobacco use had greater risks of depressive symptoms compared with unexposed offspring, suggesting early screening and prevention of these exposures could possibly reduce depressive symptoms in offspring.