OBJECTIVES: The Phase III TITAN trial (TMC114-C214) evaluated darunavir/ritonavir (DRV/r) 600/100mg bid versus lopinavir/ritonavir (LPV/r) 400/100mg bid in treatment-experienced, LPV/r-naïve, HIV-infected adults. We determined the cost-effectiveness of DRV/r versus LPV/r from the perspective of British, Swedish, Italian and Belgian payers in the TITAN trial subgroup with at least one IAS-USA primary protease inhibitor (PI) mutation at baseline. These patients had less advanced HIV disease and a broader degree of prior PI use/failure (0–=2) than those in the DRV Phase IIb POWER trials (=2). METHODS: An existing Markov model containing 6 CD4+ T-cell count (CD4 count)-defined health states and a “death” state was adapted to the abovementioned countries. Baseline demographics and CD4 count distribution, antiretroviral drug usage, virologic and immunologic response rates and matching transition probabilities were based on TITAN trial data collected in the modelled subgroup during the first 48 weeks of therapy and from published literature. Patients were assumed to switch to a follow-up combination therapy after failure. For each model state, utility values and mortality rates were obtained from published literature. Costs in each state were obtained from local observational studies and official, local unit costs or from published literature. A lifetime horizon was taken. Discount rates varied according to local guidelines. RESULTS: The base-case incremental cost-utility was €18213 (£13111)/QALY, €7605 (SEK 70379)/QALY, €17592/QALY and €7990/QALY in the UK, Sweden, Italy and Belgium, respectively. Assuming a threshold of €30,000/QALY, DRV/r remained cost-effective over most parameter ranges tested in extensive one-way sensitivity analyses. Probabilistic sensitivity analysis revealed a probability of =67% of an ICER below this threshold in all countries. CONCLUSIONS: From the British, Swedish, Italian and Belgian payer perspective, DRV/r 600/100mg bid is predicted to be cost-effective versus LPV/r in the management of LPV/r-naïve, PI-resistant, HIV-infected adults with a broad range of prior PI use/failure.