BACKGROUND: Agents for the treatment of HIV-1-infected patients with resistance to current antiretroviral (ART) drugs are needed. METHODS: TMC114-C202 was a randomized, partially blinded, dose-finding study in treatment-experienced HIV-1-infected patients with one or more primary protease inhibitor (PI) mutations and HIV-1 RNA > 1000 copies/ml. Patients were randomized to receive one of four TMC114 doses given with ritonavir (TMC114/r) or investigator-selected control PI drug(s) (CPI); all received an optimized background regimen. The primary intent-to-treat analysis compared the proportion of patients achieving a ≥1 log10 copies/ml HIV-1 RNA reduction at week 24 between the treatment arms using the time-to-loss of virological response algorithm. RESULTS: For 278 patients at baseline, mean HIV-1 RNA was 4.7 log10 copies/ml, median CD4 cell count was 106 cells/μl; HIV-1 isolates had a median of three primary PI mutations and a median fold change in lopinavir susceptibility of 80. Discontinuation rates were 23% for TMC114/r versus 64% for CPI. More patients in each TMC114/r dose group achieved ≥1.0 log10 copies/ml reduction in HIV-1 RNA than in the CPI group (45-62% versus 14%; P ≤ 0.003): patients taking TMC114/r twice daily had the greatest responses. HIV-1 RNA was < 50 copies/ml in 18-39% of TMC114/r patients versus 7% CPI (P < 0.001 for highest dose). Mean CD4 cell count increased by 59-75 versus 12 cells/μl (TMC114/r versus CPI: P ≤ 0.005). Overall adverse event rates were similar in both arms, without significant differences among TMC114/r groups. CONCLUSIONS: TMC114/r treatment resulted in greater virological and immunological responses in ART-experienced patients compared with CPI at 24 weeks. © 2007 Lippincott Williams & Wilkins, Inc.