Although discontinuation of antiretroviral drug therapy is common, the impact on outcome in routine clinical practice is unknown. The Antiprotéases Cohorte (APROCO) Cohort Study enrolled 1281 patients at the time they started a protease inhibitor (PI)-containing regimen from 1997 through 1999. After a median duration of follow-up of 20 months, 51% of patients had discontinued their initial PI. Prospectively recorded reasons for discontinuation were intolerance (52% of patients), poor adherence (22%), and failure of therapy (15%). In a multivariate logistic regression analysis, only discontinuation due to poor adherence was associated with a lower frequency of human immunodeficiency virus RNA level in plasma of <500 copies/mL 12 months after initiation of therapy (odds ratio, 0.27 vs. no change; P<.0001); discontinuation due to intolerance was not associated with virological response (odds ratio, 0.89; P=.58). Patients experiencing intolerance should be reassured that changing therapy will probably not be harmful. Multidisciplinary efforts should concentrate on ways to avoid discontinuation of treatment for adherence reasons.