Nonfatal drug overdoses are common among heroin users. While several factors that increase risk of overdose have been identified, there is little research on the role of mental health status. The purpose of this study was to examine the association between depressive symptoms and history of overdose. A sample of 729 opiate and cocaine users completed a cross-sectional survey. Of the sample, 65% reported never having overdosed, 31% had overdosed longer than 12 months before the interview, and 4% had overdosed within the past 12 months. Results indicate that a high score on the Center for Epidemiological Studies Depression Scale (CES-D), a measure of depressive symptoms, was associated with having overdosed within the past 12 months (relative risk ratio [RRR] = 3.06; 95% confidence interval [CI], 1.33 to 7.05) after adjusting for age, gender, injection frequency, and physical health impairment. These results suggest that drug users with depressive symptoms should be targeted for overdose prevention programs.