Although different factors have been implicated in the CD4/CD8 T-cell ratio recovery in HIV-infected patients who receive effective antiretroviral therapy (ART), limited information exists on the influence of the regimen composition.A longitudinal study carried out in a prospective, single-center cohort of HIV-infected patients. ART regimens including non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), or integrase strand transfer inhibitors (INSTI) from patients who achieved long-term (≥6-month duration) virological suppression (HIV-RNA < 400 copies/mL) from January 1998 to June 2014 were analyzed. The impact of ART composition on the changes of the CD4/CD8 T-cell ratio was modeled using a mixed linear approach with adjustment for possible confounders.A total of 1068 ART regimens from 570 patients were analyzed. Mean (SD) age of the patients was 42.15 (10.68) years and 276 (48.42%) had hepatitis C virus (HCV) coinfection. Five hundred fifty-eight (52.25%) regimens were PI-based, 439 (40.10%) NNRTI-based, and 71 (6.65%) INSTI-based; 487 (45.60%) were initial regimens, 476 (44.57%) simplification, and 105 (9.83%) salvage regimens. Median (IQR) number of regimens was 1 (1–2) per patient, of 29 (14–58) months duration, and 4 (3–7) CD4/CD8 measurements per regimen. The median baseline CD4/CD8 ratio was 0.42, 0.50, and 0.54, respectively, with the PI-, NNRTI-, and INSTI-based regimens (P = 0.0073). Overall median (IQR) increase of CD4/CD8 ratio was 0.0245 (−0.0352–0.0690) per year, and a CD4/CD8 ratio ≥1 was achieved in 19.35% of the cases with PI-based, 25.97% with NNRTI-based, and 22.54% with INSTI-based regimens (P = 0.1406). In the adjusted model, the mean CD4/CD8 T-cell ratio increase was higher with NNRTI-based regimens compared for PI-based (estimated coefficient for PI [95% CI], −0.0912 [−0.1604 to −0.0219], P = 0.009). Also, a higher CD4/CD8 baseline ratio was associated with higher CD4/CD8 increase in the adjusted model (P = 0.001); by contrast, higher age (P = 0.020) and simplification of ART regimen (P = 0.003) had a negative impact on the CD4/CD8 ratio.Antiretroviral regimen composition has a differential impact on the CD4/CD8 T-cell ratio; NNRTI-based regimens are associated with enhanced CD4/CD8 T-cell ratio recovery compared to PI-based antiretroviral regimens.