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The aim of this study was to describe the rates and predictors of discontinuing first-line antiretroviral therapy in the different eras of treatment over a nearly 20 year period initiated in British Columbia between 1992 and 2010.All naive adults who started antiretroviral therapy (first-line antiretroviral therapy) at any hospital or clinic in British Columbia (Canada) in 1992–2010 were included in this population-based retrospective cohort study. We were primarily interested in whether the era of treatment (1992–95, 1996–2000, 2001–05 and 2006–10) was associated with discontinuation (stopping or switching of initial treatment) within 3 years of starting therapy. Weibull survival analysis was used to model the era of treatment and its association with time to discontinuation.The study included 7901 patients. Overall, the probability of discontinuing at 12, 24 and 36 months of treatment was 52%, 68% and 76%, respectively. In the adjusted model, variables associated with discontinuing were earlier treatment era, younger age, low adherence and lower baseline CD4 count. Regarding the 2006–10 period, the probability of discontinuing at 12, 24 and 36 months was 36%, 47% and 53%, respectively. In the adjusted model, the variables associated with discontinuation were younger age, female gender, AIDS-defining illnesses at baseline, low adherence and a protease inhibitor (PI)-based regimen.Discontinuation rates of first-line therapy have decreased over time, but are still quite high even for the latest drug combinations. In the most recent era, younger women on a PI regimen and those not achieving optimal adherence had the highest risk of discontinuing first-line antiretroviral therapy.