BACKGROUND:we explored predictors of CD4/CD8 ratio improvement and optimal immunological recovery (OIR) after initiation of antiretroviral therapy(ART) in naïve people living with HIV (PLWH). METHODS:Retrospective multicenter study including naïve PLWH starting ART with 2NRTIs + one InSTI or NNRTI or PI. PLWH were followed from the time of ART initiation (baseline) to the discontinuation of first-line regimen, virological failure, death or loss to follow-up. Estimated incidence and predictors of time to CD4/CD8 ratio normalization (defined as ≥1) and OIR (defined as CD4/CD8 ratio≥1 plus CD4≥500cells/µL plus CD4%≥30%) were explored by Kaplan Meier curves and Cox regression analysis. RESULTS:Overall, 1428 PLWH (77.8% males, median age 39 years, 55.1% with positive CMV antibodies, median HIV-RNA 4.80 log copies/mL, median CD4 323cells/µL, median CD4/CD8 ratio 0.32) were included, of which 21.5%(n=307), 44.5%(n=636) and 34%(n=485) treated with InSTI-, PI- and NNRTI-based regimens, respectively. The estimated proportion of CD4/CD8 normalization and OIR at 36 months was 38.6% and 32.9%, respectively. Multivariate analysis showed that InSTI-based regimens had a higher probability of CD4/CD8 ratio normalization and OIR both in the total population(p<0.001 versus PI) and in advanced naïve PLWH (p≤0.001 versus PI and NNRTI). Moreover, subjects with positive CMV serology showed a lower probability of CD4/CD8 ratio normalization and OIR(p<0.001). CONCLUSIONS:InSTI-based regimens showed a better immune recovery, suggesting that the type of first-line ART can influence immune reconstitution. PLWH with positive CMV serology showed an increased risk of suboptimal immune recovery.