Objective: To assess the efficacy and tolerability of a triple nucleoside reverse transcriptase inhibitor combination of zidovudine, lamivudine, and didanosine therapy.Design: A randomized open-label trial.Patients: Antiretroviral-naive HIV-infected patients with CD4+ cell counts of 100 to 500 cells/μl.Methods: A total of 106 patients were randomly assigned to 300 mg of zidovudine (200 mg for body weight <60 kg) twice daily plus 150 mg of lamivudine twice daily plus 200 mg of didanosine (125 mg for body weight <60 kg) twice daily (n = 53) or to zidovudine plus lamivudine (n = 53) for 48 weeks.Main Outcome Measures: Degree and duration of reduction of HIV-1 RNA load and increase in CD4+ cell counts from baseline and development of drug-related toxicities.Results: At 48 weeks, triple drug therapy showed greater declines in plasma HIV-RNA levels from the beginning of treatment than double drug therapy (1.86 vs. 1.15 log10 copies/ml, respectively;p < .001). The proportions of patients with HIV-RNA <50 copies/ml in an intention-to-treat analysis were 54.7% (29 of 53 patients) and 11.3% (6 of 53 patients) in the triple and double drug therapy, respectively (p = .001). There was no significant difference in increase of CD4 count.Conclusion: Triple drug therapy with zidovudine, lamivudine, and didanosine was significantly more effective in inducing sustained immunologic and virologic responses than the double combination of zidovudine and lamivudine.