OBJECTIVES The ritonavir-boosted protease inhibitor (PI/r) darunavir (darunavir/r) 800/100 mg QD has recently been licensed in the US for use in treatment-naïve HIV-infected adults. The objective of this study was to compare the cost and efficacy of darunavir/r-based triple therapy with other combination therapies using PI/rs currently licensed for this patient population in the US. METHODS Virologic efficacy was measured by the percentage of individuals with plasma HIV RNA <50 copies/mL (the current goal of antiretroviral therapy) at 48 weeks, based on a systematic review of clinical trials of PI/r-based regimens in treatment-naïve populations. One-year antiretroviral therapy costs were calculated in 2008 US dollars. The base-case analysis considered PI/rs with a tenofovir-based backbone regimen; an abacavir-based backbone was considered in scenario analysis. RESULTS The base-case analysis showed that darunavir/r was the most efficacious PI/r, with an incremental cost-efficacy ratio (ICER) of $31,524 per additional individual with virologic response, when compared with fosamprenavir/r, the only other point on the efficiency frontier of PI/r-based initial therapy. All other PI/rs were less efficacious and more costly than darunavir/r or fosamprenavir/r, including the two most commonly prescribed: atazanavir/r and lopinavir/r. Before the introduction of darunavir/r, atazanavir/r was most efficacious but with a higher ICER of $46,612 compared with fosamprenavir/r. Darunavir/r has an average cost of $25,059 per individual with virologic response, compared with $25,880 and $26,526 for atazanavir/r and lopinavir/r, respectively. Given a fixed budget of $10 million, darunavir/r successfully treats 399 individuals, compared with 386 and 377 for atazanavir/r and lopinavir/r, respectively. Similar results were obtained in scenario analysis using an abacavir-based backbone. CONCLUSIONS Darunavir/r 800/100 mg QD has a lower cost per individual with virologic response after 48 weeks than the 2 most commonly prescribed PI/rs in treatment-naïve, HIV-infected adults and provides more benefit per additional cost than other currently available PI/rs.