BACKGROUND Previous studies have evaluated the simplification of HIV treatment with ritonavir-boosted protease inhibitor monotherapy, demonstrating acceptable efficacy and advantages such as avoidance of the adverse effects of reverse transcriptase inhibitors. To achieve the best results, patients should be appropriately selected for this therapy. OBJECTIVE The purpose of this study was to estimate the proportion of HIV patients suitable for boosted protease inhibitor monotherapy according to clinical trial criteria. Setting The study was conducted in the outpatient hospital pharmacy service of the Complejo Hospitalario de Navarra in northern Spain. METHODS A retrospective analysis was performed on data from 635 adults on antiretroviral therapy. The eligibility criteria were: (1) >18 years of age; (2) prior triple-drug antiretroviral regimen; (3) durability of current treatment >18 months; (4) viral load <400 copies/mL over the 18 months before evaluation and <50 copies/mL over the last 6 months; (5) CD4 count ≥250 cells/μL; (6) CD4 count nadir >100 cells/μL; (7) no previous virological failure under prior protease inhibitor-based regimen; (8) absence of co-infection with hepatitis B virus; (9) absence of HIV-related neurological disease; and (10) adherence >95 %. The average cost of the current treatment was calculated for patients who met all criteria, as well as the potential economic impact of simplification to monotherapy. METHODS Number of patients meeting all criteria for simplification to monotherapy according to clinical trial standards. RESULTS One hundred and three patients (16.5 %) met the clinical trial criteria for protease inhibitor monotherapy. One hundred and fifty patients (24 %) failed to fulfil only one of the conditions. Fifty-four percent of the patients who met all of the criteria had been treated for more than 10 years. The average saving per patient per year was <euro>2,850-<euro>3,400. CONCLUSIONS This treatment strategy represents a realistic, albeit minority, option. Fulfilment of the above conditions should be the basis for simplification to protease inhibitor monotherapy, though the final decision depends on clinical criteria and patient preferences assessed by the attending physician. Further studies are needed to confirm long-term safety and efficacy.