Gender differences in a large population-based cohort of HIV-1 infected patients (245 women and 723 men) were examined with respect to the incidence of metabolic and morphologic alterations after initiation of highly active antiretroviral therapy (HAART). Patients initiated HAART between January 1996 and December 2003. The outcome measures were the incidence of hyperglycemia, hypercholesterolemia, symptomatic lactic acidosis, treatment-limiting lipodystrophy, and hypersensitivity reaction. Cox proportional hazards models were used to estimate the crude and adjusted hazard ratios of reaching the endpoints for exposures and covariates. Women were younger than men (35 +/- 9.8 vs. 40 +/- 8.2 years, P < 0.001) and more frequently from Haiti or Africa (59%), whereas 76% of men were Canadian-born. Type of initial HAART regimen did not differ between women and men. There were no gender differences in the overall incidence of hyperglycemia, hypercholesterolemia, or treatment-limiting lipodystrophy, even after adjusting for age, CD4 cell count, viral load, time since HIV diagnosis, history of AIDS-defining illness and year of HAART initiation. In contrast, women had significantly higher risk of developing lactic acidosis than men (P = 0.0009). Hypersensitivity reactions were also more frequent in women than men (adjusted hazard ratio = 4.4 (95% CI: 2.1-9.3)). Collectively, these data suggest that metabolic toxicities after HAART do not differ by gender but that lactic acidosis and hypersensitivity reactions are more frequent in women than men.