Objective: The aim of this study was to observe the effect of sex on attaining optimal adherence to combination antiretroviral therapy (cART) longitudinally while controlling for known adherence confounders-IDU and ethnicity. Design: Using the population-based HAART Observational Medical Evaluation and Research cohort, data were collected from HIV-positive adults, aged at least 19 years, receiving cART in British Columbia, Canada, with data collected between 2000 and 2014. cART adherence was assessed using pharmacy refill data. The proportion of participants reaching optimal (>= 95%) adherence by sex was compared per 6-month period from initiation of therapy onward. Generalized linear mixed models with logistic regression examined the effect of sex on cART adherence. Results: Among 4534 individuals followed for a median of 65.9 months (interquartile range: 37.0-103.2), 904 (19.9%) were women, 589 (13.0%) were Indigenous, and 1603 (35.4%) had a history of IDU. A significantly lower proportion of women relative to men were optimally adherent overall (57.0 vs. 77.1%; P< 0.001) and in covariate analyses. In adjusted analyses, female sex remained independently associated with suboptimal adherence overall (adjusted odds ratio: 0.55; 95% confidence interval: 0.48-0.63). Conclusion: Women living with HIV had significantly lower cART adherence rates then men across a 14-year period overall, and by subgroup. Targeted research is required to identify barriers to adherence among women living with HIV to tailor women-centered HIV care and treatment support services.