Objectives: There are scarce data on the combination of dolutegravir (DTG) plus rilpivirine (RPV) in the real world, including patients with hepatitis C virus (HCV) coinfection, toxicity or previous failure, or at risk for severe drug-drug interactions (DDIs). Methods: Prospective cohort study of virologically suppressed HIV-1 infected patients, without resistance to DTG or RPV, switched to this dual regimen because of toxicity or risk of DDIs (NCT02491242). Results: Overall, 102 patients (mean age 54 years, 28% women) were included. Fifty-seven were coinfected with HCV (fibrosis grade 4 in 27 cases, 1 liver transplantation). Seven patients had chronic kidney disease (1 renal transplantation). At week 48, only 1 virologic failure occurred (<1%), and 6 patients (6%) left the regimen (3 with central nervous system adverse events, 1 each due to pregnancy, metformin interaction, and lost to follow up). Thus, the overall treatment success rates were 93% (95% CI, 88%-98%; ITT-e, snapshot analysis) and 96% (95% CI, 92%-99%; per protocol analysis). The CD4/CD8 ratio increased slightly (median, +0.03). Triglycerides levels improved significantly (-18.8%, p < 0.01). The creatinine-based estimated glomerular filtration rate decreased by a mean of -8.4 ml/min/1.73 m2, but tubular renal parameters improved. A paired dual X-ray absorptiometry scan showed a mild improvement in spine (mean, +1.15%; -0.57 to +3.3%) and in femoral neck bone mineral density (mean, +0.4%; -3.3% to +2.57%). Conclusions: In the clinical setting, switching to the combination of DTG plus rilpivirine in virologically suppressed HIV-1 patients is effective and safe, and improves lipid, renal and bone evolution.