BACKGROUND: We hypothesized that rates and reasons for treatment modifications have changed since the implementation of combination antiretroviral therapy (cART) due to improvements in therapy. METHODS: From a nationwide population-based cohort study we identified all HIV-1 infected adults who initiated cART in Denmark 1997-2009 and were followed (3)1 year. Incidence rate ratios (IRR) and reasons for treatment modifications were estimated and compared between patients, who initiated treatment in 1997-1999, 2000-2004 and 2005-2009. Rates of discontinuation of individual antiretroviral drugs (ARVs) were evaluated. RESULTS: 3,107 patients were followed median 7.3 years (IQR 3.8-10.8). Rates of first treatment modification ≤1 year after cART initiation did not change (IRR 0.88 (95% CI 0.78-1.01) and 1.03 (95% CI 0.90-1.18) in 2000-2004 and 2005-2009 compared to 1997-1999). Rates of multiple modifications decreased markedly (2000-2004: IRR 0.60 (95% CI 0.53-0.67) and 2005-2009 0.38 (95% CI 0.32-0.46)). Rates of treatment modifications due to virological failure, toxicity and other/unknown reasons decreased (IRR 0.25 (95% CI 0.14-0.45), 0.69 (95% CI 0.56-0.83) and 0.45 (95% CI 0.36-0.57) in 2005-2009 compared to 1997-1999), while the rate of modifications with the aim of simplification increased (IRR 1.85 (95% CI 1.52-2.25)). CONCLUSIONS: Rates of first treatment modification ≤1 year after cART initiation have not changed since the early cART era, while the risk of multiple modifications has decreased markedly. Modifications due to virological failure and toxicity have decreased substantially, while rates of switch to simpler and less toxic regimens have increased.