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To compare adherence and clinical outcome with two modalities of highly active antiretroviral therapy (HAART), in HIV-infected patients.Randomized, open-label, prospective study.Tertiary care centre in Spain.A total of 112 non-naive HIV-infected patients, recruited from March 1998 through August 1998, were studied.Triple drug therapy with stavudine and lamivudine, plus indinavir or nelfinavir.Adherence, side-effects, and immunological, virological, and clinical efficacy of treatment were assessed at 3-month intervals.After a median follow-up of 9 months, 32% of patients in the indinavir group versus 50% of those in the nelfinavir group showed adequate adherence in all clinical appointments (P = 0.0559). Adherence was superior in the nelfinavir group in every visit. After 6 months of treatment 48% of subjects in the indinavir group and 70% of those in the nelfinavir group exhibited adequate adherence (P = 0.0311). After 9 months 35% of patients in the indinavir group and 59% of those in the nelfinavir group showed adequate adherence (P = 0.0291). Side-effects provoked discontinuation of treatment in 34% of patients in the indinavir group and 12% of patients in the nelfinavir group (P = 0.0073). Immunological and virological efficacy were similar in both groups.Adherence to a HAART regimen with stavudine plus lamivudine plus nelfinavir was superior to a regimen with stavudine plus lamivudine plus indinavir. Side-effects provoked more discontinuation of treatment in the indinavir group than in the nelfinavir group.