BACKGROUND: Here, we aimed to evaluate regional differences in all-cause, AIDS- and non-AIDS-related mortality in HIV-positive men and women started on combination antiretroviral therapy (cART) in Europe, Canada and the US. METHODS: The ART Cohort Collaboration (ART-CC) combines 19 cohorts of individuals started on cART in Europe and North America (NA). We analysed patients infected via injecting drug use (IDU) or heterosexual sex using Cox proportional hazards models. RESULTS: A total of 32,443 European (45.9% women), 1,162 (32.5% women) Canadian and 2,721 (15.5% women) US patients were included. In Europe and NA, women were younger, more likely to have acquired HIV heterosexually, be AIDS-free and have higher CD4(+) T-cell counts and lower HIV-1 RNA at baseline. European women had lower rates of all-cause (adjusted hazard ratio: 0.76; 95% CI 0.68, 0.84) and non-AIDS mortality (0.67; 0.57, 0.78) than men, but AIDS-mortality rates were similar (0.90; 0.75, 1.09). Women had lower mortality due to non-AIDS infections (0.6 versus 1.3 per 1,000 person-years), liver diseases (0.4 versus 1.7), non-AIDS malignancies (0.6 versus 2.0) and cardiovascular diseases (0.6 versus 1.0). Between-sex differences in all-cause mortality were larger in heterosexuals (0.70; 0.61, 0.80) than in IDU (0.88; 0.73, 1.05; interaction P-value =0.043). No sex differences in all-cause mortality were found in Canada (hazard ratio women 1.13; 0.82, 1.56) or US (hazard ratio women 1.12; 0.79, 1.58). CONCLUSIONS: The increasing importance of non-AIDS mortality is leading to emergent sex differences among HIV-positive patients in Europe, as in the general population. Despite the better clinical characteristics at cART initiation, women in NA had similar mortality to men.