OBJECTIVES: Many patients have simplified their therapy by replacing protease inhibitors (PI) with efavirenz. In a large cohort study representative of clinical practice, we compared outcomes in patients who replaced PI with efavirenz (switchers), with patients who continued on PI (non-switchers). We investigated the likelihood of virological failure in switchers and non-switchers, and the tolerance of efavirenz-containing regimens in different transmission risk groups. DESIGN, SETTING, AND METHODS: Using the database of the Swiss HIV Cohort Study, we identified patients who switched from PI-containing to efavirenz-containing highly active antiretroviral therapy for reasons of tolerance, toxicity, or convenience. Switchers were matched to non-switchers on the basis of calendar time, CD4 cell count, and viral load. RESULTS: The probability of virological failure was less in patients who switched to efavirenz values after one year: 9.4% [95% confidence interval (CI) 5.5-15.9] versus 27.2% (95% CI 21.5-34.1), odds ratio (OR) for failure 0.34. The effect was more pronounced when injection drug users (IDU) were omitted from the analysis (OR 0.19, 95% CI 0.09-0.43); it was absent in IDU (OR 0.95, 95% CI 0.44-2.04). IDU stopped efavirenz more frequently during the first 2 months of treatment than non-IDU [22.6% (95% CI 11.5-41.6) versus 6.6% (95% CI 3.6-11.8) at 2 months]. No difference between IDU and non-IDU was evident when the frequency of stopping indinavir or nelfinavir was measured. CONCLUSION: Switchers had less virological failure and less chance of further treatment changes than non-switchers. However, efavirenz was less successful in IDU than in other transmission categories.