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Abstract: Background: Assessing factors associated with non-fatal overdose is important as these could be useful to identify individuals with substance use disorders at high risk of adverse outcomes and consequences. Depression may play an important role in terms of overdose risk. We aimed to test if drug users suffering from a depressive disorder might have significantly higher risk of non-fatal overdose as compared with drug users without depression. Methods: We conducted a systematic review and meta-analysis. PubMed, Embase and Web of Knowledge were searched. The pooled analyses were based on prevalence rates, risk difference (RD) and odds ratio (OR), reporting 95% confidence intervals (CIs). The combined estimates were obtained weighting each study according to random effects model for meta-analysis. Results: Seven articles, involving 12,019 individuals, and run in the US, Canada, Sweden, Norway, and Australia, were included. Pooled analyses comparing depressed with not depressed individuals highlighted a RD (95% CIs) for non-fatal overdose of 7.3% (4.8–9.7%) and an OR (95% CIs) of 1.45 (1.17–1.79). The subgroups analyses based on specific characteristics of included studies confirmed the association between depression and overdose. Conclusions: Depressive disorders seem to be important factors associated to the risk of non-fatal overdose. Longitudinal studies might appropriately clarify causal inference issues. Future research should address the role of depressive disorders as predictors of subsequent non-fatal overdoses. [Copyright &y& Elsevier]