Abstract Background Raltegravir (RAL) has favorable tolerability and safety profile, with few and manageable drug interactions. The use of RAL 1200~mg once daily (qd) for first-line therapy is well established. We assessed efficacy and safety of RAL 1200~mg qd, as part of triple combined antiretroviral therapy (cART), for maintenance strategy. Methods The QDISS trial (NCT03195452) was a 48-week multicenter, single-arm, open-label study designed to evaluate the ability of 2 NRTIs\,+\,RAL 1200~mg qd to maintain virological suppression in HIV-1 infected subjects on a stable cART with 2 NRTIs and a third agent for at least 6~months. The primary endpoint was the proportion of participants with HIV-1 RNA\,<\,50 copies/mL at week 24, by the FDA snapshot algorithm. Results Of 100 participants 91% maintained viral suppression (95% CI: 83.6\textendash 95.8) at week 24 and 89% (81.2\textendash 94.4) at week 48. At week 24, there was one virological failure, without emergence of resistance-associated mutation and 10 participants had discontinued, 4 because of adverse events (AEs). Over 48~weeks, 7 AEs of grade 3\textendash 4 were reported, one possibly study-drug related (spontaneous abortion). BMI remained stable regardless of previous therapy or baseline BMI category. Over 48~weeks, total cholesterol ( p \,=\,0.023) and LDL-cholesterol ( p \,=\,0.009) decreased, lifestyle and ease subscale significantly improved ( p \,=\,0.04). The quality of life and Patients Reported Outcomes (PROs) also improved at W12 ( p \,=\,0.007). Conclusion RAL 1200~mg qd as part of a maintenance triple therapy showed a high efficacy in virologically suppressed HIV-1 infected subjects, with good safety profile and improved lipid profile and patient reported outcomes. Trial registration: Clinical trials.gov NCT03195452 and EudraCT 2016-003702-13.