To evaluate the safety, tolerability, and anti-HIV activity of ritonavir-nelfinavir (RTV-NFV). Single-site, open-label, nonrandomized, multiple-dose trial of RTV combined with two doses of NFV in protease inhibitor (PI)-naive, HIV-infected patients. Mean baseline HIV RNA was 39,500 copies/ml; mean baseline CD4 count was 323 cells/mm3. All patients received RTV at a dosage of 400 mg twice daily. Cohorts I (N = 10) and II (N = 10) received NFV at a dosage of 500 mg and 750 mg twice daily, respectively, for the initial 12 weeks of the study before allowing intensification with reverse transcriptase inhibitors. The commonest effects of RTV-NFV therapy were study drug-related moderate-to-severe diarrhea (9 patients in cohorts I and II) and drug-related moderate-to-severe nausea (4 patients in cohorts I and II). HIV RNA was suppressed in a biphasic manner. At 48 weeks in cohort I, mean HIV RNA reduction was 2.82 log10 copies/ml (standard error [SE] =.61; p =.001; N = 4); mean CD4 cell count increase was 236 cells/mm3 (SE = 67.1; p =.006; N = 4). In cohort II, mean HIV RNA reduction at Week 48 was 2.21 log10 copies/ml (SE =.430; p =. 001; N = 8); mean CD4 cell count increase was 120 cells/mm3 (SE = 47. 5; p =.03; n = 8). In cohort I patients, 2 of 4 completing Week 48 had HIV RNA <20 copies/ml; and 3 of 4 had HIV RNA <400 copies/ml. In cohort II, 2 of 8 patients completing Week 48 had HIV RNA <20 copies/ml and 4 of 8 had HIV RNA <400 copies/ml. In addition, 3 patients in cohort I withdrew because of virologic failure not thought to be related to poor compliance. Moreover, 15 patients elected to add new reverse-transcriptase inhibitors (RTIs) after week 12. RTV-NFV with concomitant reverse transcriptase inhibitors is a potential dual-PI option for PI-naive patients.