Background Boosted-protease inhibitors (b-PIs) are not recommended for initial therapy in HIV patients, but there is still a cohort of patients who could benefit from this antiretroviral treatment (ART). The purpose of this study was to analyze the profile of HIV patients who receive for the first time an ART containing two nucleoside reverse transcriptase inhibitors (NRTIs) and one b-PI. Efficacy and safety of this treatment, as well as the reasons for starting and changing it, were evaluated. Methods An observational, retrospective study was performed on the use of b-PIs in adult HIV patients. Individuals who started treatment with two NRTIs (emtricitabine and tenofovir alafenamide) and one b-PI (darunavir combined with cobicistat or ritonavir) between October 2019 and September 2021 were eligible for our study. This study was retrospectively registered by local Ethics Committee of our hospital (protocol number: PI-5066) on January 13th 2022. Results Overall, 52 patients started ART with two NRTIs plus one b-PIs. Only 8% of them were naïve, 21% received already two NRTIs plus a b-PI and 71% received other regimens. Reasons to start PIs were adverse effects to previous treatment and previous treatment failure. Most patients continued PIs treatment during the 2 years follow-up period and only six of them withdrew it. Conclusions This study analyzes the subgroup of patients that could benefit from treatment with b-PIs in the current era of integrase inhibitors. Even though its use is minority, its efficacy is high especially in patients with toxicity, therapeutic failure or poor adherence to other ARTs.