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Background Given the gendered distribution of depression, this paper aims at exploring the gender disparities in the effect of depression on condom use in last sexual intercourse in a nationally representative sample of sexually active Canadians. Methods Data in this study came from the Canadian Community Health Survey 2009–2010 ( n =124,188 aged ≥12 years). The analysis in this study was restricted to 7238 respondents aged 15–49 years who had sexual intercourse in the 12-months preceding the survey. Multivariable logistic regression, stratified by gender, was used to estimate the effect of depression on condom use adjusting for potential confounders. Results Reported condom use was lower in females (46.9%) than in males (60.9%), while depression was more in females (13.5%) than in males (8.4%). Condom use was less among people with depression, in both males and females. However, condom use was far less frequent among females (41.2%) with depression than their male counterparts (58.1%). Depression was found to reduce the odds of condom use in last sexual intercourse both in males and females. However, the effect was statistically significant in females only (adjusted odds ratio: 0.81; 95% CI: 0.66–0.99). Limitations Cross-sectional data, and inability to capture socio-economic status and alcohol use rigorously are some of the limitations of this study. Conclusions Depression was found to reduce condom use significantly in females. Public health programs aimed at increasing condom use should address the issues of improving self-efficacy in condom negotiation skills in females, along with addressing mental health issues, especially depression, with a gender-sensitive perspective. [ABSTRACT FROM AUTHOR]