Despite the relative lack of data, nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-sparing regimens are increasingly prescribed in clinical practice in treatment-experienced HIV-1 infected patients. We aimed to assess the frequency of NRTI-sparing regimens among these subjects, and to evaluate and compare their safety and tolerability. Patients were included if enrolled in the currently ongoing cohorts (raltegravir and darunavir) of the Surveillance Cohort Long-Term Toxicity Antiretrovirals (SCOLTA) Project. The duration of treatment with antiretroviral therapy was evaluated using the Kaplan-Meier curve and NRTI-sparing and NRTI-based regimens were compared using the log-rank test. From 2006 to 2011, 689 experienced patients were analyzed, of whom 210 (30.5%) were on NRTI-sparing regimens. Patients on NRTI-sparing regimens were older (p=0.004) and had higher median CD4+ cell counts (p=0.002) than patients on NRTI-based regimens. The most frequent combination regimens were raltegravir plus darunavir/ritonavir (n=65; 30.95%) among patients on NRTI-sparing regimen and tenofovir DF/emtricitabine plus darunavir/ritonavir in the NRTI-containing group (n=102; 21.3%). There was no difference between groups in terms of total withdrawal, treatment discontinuation was more likely due to therapeutic failure in NRTI-sparing regimen. NRTI-sparing regimens should be evaluated in a prospective randomized trial.