OBJECTIVES: To compare the cost and efficacy of ritonavir-boosted darunavir (darunavir/r) 800/100 mg QD-based triple therapy with combination therapies using other boosted protease inhibitors (PI/rs) currently licensed for use in treatment-naïve, HIV-1-infected adults in Germany. METHODS: Efficacy was measured by the percentage of individuals with plasma HIV RNA <50 copies/mL (the current therapy goal) at 48 weeks, based on a systematic review and meta-analysis of clinical trials of PI/r-based regimens in treatment-naïve populations. For each PI/r, one-year antiretroviral therapy costs (May 2009 Lauer Taxe) were plotted against 48-week efficacy. An efficiency frontier was constructed by connecting the most economically efficient PI/r-based regimens. The base-case analysis considered PI/rs with tenofovir-based backbone regimens; abacavir-based backbones were considered in scenario analysis. RESULTS: In the base-case analysis, darunavir/r was the most efficacious PI/r, with an incremental cost-efficacy ratio (ICER) of €20,322 per additional individual with virologic response, compared to 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 PI/rs: atazanavir/r and lopinavir/r. Before the introduction of darunavir/r, atazanavir/r was most efficacious but with a higher ICER of €34,244 versus fosamprenavir/r. Darunavir/r had an average cost of €20,036 per individual with virologic response, compared with €20,976 and €22,861 for atazanavir/r and lopinavir/r, respectively. Given a fixed budget of €10 million, darunavir/r successfully treated 499 individuals, compared with 477 and 437 for atazanavir/r and lopinavir/r, respectively. Similar results were obtained in scenario analysis using abacavir-based backbones. CONCLUSIONS: Darunavir/r 800/100 mg QD has a lower cost per individual with virologic response after 48 weeks than the two most commonly prescribed PI/rs in treatment-naïve, HIV-1-infected adults and provides more benefit per additional cost than other PI/rs currently used in this population in Germany.