We evaluated the frequency of and reasons for discontinuation of protease inhibitor therapy in a cohort of HIV-infected patients in a prospective observational study. We included 230 HIV-infected patients who had started protease inhibitor therapy between November 1996 and July 1997. Mean baseline CD4 count was 138 cells/microl and HIV-RNA 4.5 log10. Forty-five percent of patients had prior AIDS and 77% had been treated with nucleoside analogues. Saquinavir-treated patients were at a less advanced stage of HIV disease. Overall, 41.3% of patients discontinued therapy, and their last HIV-RNA measured higher than that of patients who continued therapy: 4.07 vs. 2.70 log10 (p < 0.0001). Reasons for discontinuation of therapy were poor adherence (including abandonment) (18.6%), drug intolerance (12.1%), virological failure (7%) and physician decision (3.5%). In a multivariate model, factors associated with drug discontinuation were not taking indinavir (OR 0.26, 95% CI 0.12-0.59) and being pretreated with nucleoside analogues (OR 3.42, 95% CI 1.58-7.42). We concluded that in routine clinical practice a high proportion of patients discontinued protease inhibitors during the first 6 months of therapy, the main reason being the patient's own decision (abandonment or poor adherence). Psychological support and counselling are warranted in patients when initiating protease inhibitor therapy.