OBJECTIVES: The aim of the study was to compare the highly active antiretroviral therapy either with ritonavir (RTV)/saquinavir (SQV), lopinavir/ritonavir (LPV/RTV), indinavir (IDV), nelfinavir (NFV) or efavirenz (EFV) in combination with two nucleoside reverse transcriptase inhibitors therapy. METHODS: The cost-effectiveness analysis was conducted. Clinical data were derived from published clinical trials and large observational cohorts. The analysis was based on the drug costs solely, obtained from National AIDS Centre in Poland. Three scenarios were investigated in the research. The first one extended over a time of 48 weeks of the treatment with a studied NNRTI or PI. A measure of effectiveness was defined as a virological suppression of serum HIV-RNA<400 copies/mL at the end of the treatment. In the second scenario the initial therapy for HIV infection could be switched twice in patients who failed their PI- or NNRTI-based treatment regimen. The time horizon of the analysis was set to 144 weeks, i.e. 3 cycles - 48 weeks each. A measure of effectiveness was defined as virological suppression at any point of time during the whole time horizon. In the third scenario the time horizon lasted for 10 cycles (480 weeks) of HIV-infection treatment, with two changes of treatment regimens in case of failure. In this scenario the measure of effectiveness was defined as a number of cycles with a serum HIV-RNA<400 copies/ml. RESULTS: LPV/RTV proved to be the most cost-effective combination in the first two scenarios having the cost-effectiveness ratio (C/E ratio) of 22987 PLN (Polish zlotys) and 23594 PLN, respectively. In the third scenario EFV was the most cost-effective therapy with a C/E ratio of 15254 PLN. The sensitivity analysis turned out in all scenarios the combination LPV/RTV had the smallest standard error of C/E ratio proving to be more attractive. The sensitivity analysis proved the robustness of the obtained results against the assumptions taken. CONCLUSIONS: Depending on the scenario presumed either the therapy containing LPV/RTV or EFV is the most cost-effective alternative of the treatment of HIV-infection in Poland.