BACKGROUND: Knowledge concerning the long-term antiretroviral and immunological efficacy of protease inhibitors in children is limited. PATIENTS AND METHODS: An open-label, prospective, multicenter clinical trial was conducted over a period of 72 weeks in Switzerland. 60 HIV-1 infected children (aged 0.3-16.9 years) naive to protease inhibitors were enrolled. Ritonavir or nelfinavir and at least one new nucleoside reverse transcriptase inhibitor were introduced into the current treatment regimen. HIV-1 RNA levels and CD4 cell counts were monitored after introducing the protease inhibitor, and the tolerability and safety of the drugs were assessed. RESULTS: Dictated by chronological availability, 37 children received ritonavir and 23 nelfinavir. At baseline, children given ritonavir had higher mean plasma HIV-1 RNA levels (5.03 vs 4.63 log10 copies/ml; p = 0.001) and lower mean CD4 cell counts (277 vs 555 cells/microl; p = 0.009) than children given nelfinavir. Antiretroviral treatment (ART) naive children showed higher mean plasma HIV-1 RNA levels than non-naive (5.18 vs 4.64 log10 copies/ml; p = 0.02).The decline in plasma HIV-1 RNA levels 72 weeks after treatment with ritonavir and nelfinavir was -2.17 and -1.30 log10 copies/ml, respectively (p = 0.006) and in ART-naive vs non-naive patients -2.70 vs -1.39 log10 copies/ml (p < or = 0.01). 69% of ART-naive patients and 32% of non-naive patients achieved sustained plasma HIV-1 RNA levels < 400 copies/ml. Increases in CD4 cells were higher in ART-naive compared to non-naive patients (p < 0.04). CONCLUSION: The antiretroviral and immunologic benefits of protease inhibitors are more profound in ART-naive than in non-naive children.