OBJECTIVES Single-Tablet Regimens (STR) therapies are effective to maintain high adherence and improves HAART efficacy. METHODS We evaluated viro-immunologic outcomes, Quality of Life (QoL),  and costs of an unselected cohort of patients switching from TDF/FTC/EFV STR (≥6 months duration) to TDF/FTC/RPV STR. The considered outcome measures were quality-adjusted life years (QALYs) as measured with the EQ5D questionnaire and the overall direct health costs. 64 patients with a baseline viral load < 50 copies/ml were randomized to immediately switch therapy or to continue TDF/FTC/EFV for 4 months and then switch to TDF/FTC/RPV. 6 patients in the deferred switch group did not change cART. RESULTS Patients were mostly males (73.4%) with a mean age of 46 years, a baseline mean HIV-RNA of 6.42 copies/ml and a mean baseline CD4 count of 588 cells/μL. The mean cost per patient resulted € 2,563 for STR with RPV arm and € 2,572 for STR with EFV arm. After 4 months the mean per patient  QALYs was 0.849 and 0.841 respectively. Viremia remained undetectable and CD4 stable in all patients. Additionally, other parameters such as Cholesterol, HDL and Triglycerides levels improved when switching from STR-containing EFV to Rilpivirine-based STR. VAS analysis of health status perception also increased overall from 82.78 to 83.79 (scale : 0-100) due to the improvement in the STR-containing RPV arm. STR with RPV dominated (i.e. was more effective and less costly) EFV STR regimen, as measured by outcomes. CONCLUSIONS Switching from STR containing Efavirenz to STR containing Rilpivirine is a safe, well tolerated strategy that improves the overall health status of HIV–treated patients. The switch does not expose patients to a risk of virologic failure due to possible PK interactions of the drugs. RPV compared to EFV resulted cost-effective showing lower cost and higher outcome measure values.