Objective. - To compare the safety and efficacy of 2 doses of lamivudine given in combination with zidovudine with continued zidovudine monotherapy. Design. - Double-blind, randomized, multicenter, comparative trial of 223 patients treated for 24 weeks. Setting. - Patients from 32 hospitals in Europe were enrolled throughout a 1-year period. Patients. - Adult human immunodeficiency virus type 1 (HIV-1)-positive, zidovudine-experienced (≤24 weeks prior zidovudine) patients with CD4+ cell counts between 0.10 and 0.40x109/L (100-400 cells/μL). Intervention. - Patients received either 200 mg of zidovudine every 8 hours, 150 mg of lamivudine every 12 hours plus zidovudine, or 300 mg of lamivudine every 12 hours plus zidovudine for 24 weeks. All patients were then allowed to receive zidovudine and open-label lamivudine combination therapy. Twelve patients withdrew because of adverse events during the 24-week treatment period. Main Outcome Measures. - Efficacy was measured by evaluating immunological and viral load changes, and safety was assessed by evaluating clinical manifestations and laboratory indexes of toxic effects. Results. - Patients receiving low- or high-dose combination therapy had greater treatment effects compared with patients receiving continued zidovudine monotherapy during the first 24 weeks as documented by changes in CD4+ cell counts (+0.04 vs +0.03 vs -0.02x109/L, respectively; P<.001); log10 HIV-1 RNA as measured by the Roche assay (-0.96 vs -0.77 vs +0.07 copies/mL, respectively; P<.001) or log10 HIV-1 RNA measured by the quantitative nucleic acid sequence-based amplification assay (-0.59 vs -1.06 vs -0.02 copies/mL, respectively; P<.011); and immune-complex dissociated (ICD) p24 antigen (-74% vs -68% vs +27%, respectively; P<.001). There were no statistically significant differences in viral measurements, in CD4+ cell counts, or in safety profile between the groups receiving 2 doses of lamivudine in combination with zidovudine. The effects on CD4+ cell counts and ICD p24 antigen were sustained throughout 48 weeks for patients continuing combination therapy. Patients switching to combination therapy at week 24 showed improvement. Conclusions. - In zidovudine-experienced HIV-1- infected patients, combination treatment with lamivudine and zidovudine is well tolerated and provides greater and more sustained increases in CD4+ cell counts and decreases in viral load than continued zidovudine monotherapy.