Background: CD4+ count increase has been reported to be different with lopinavir/r (LPV/r) and efavirenz (EFV)-containing regimens. The different effect of these two regimens on other immune function parameters and the relationship with the gain of CD4+ count have not been assessed in a randomized clinical trial. Methods: Fifty antiretroviral (cART) naïve-HIV-infected individuals were randomized to receive LPV/r or EFV both with tenofovir/emtricitabine during 48 weeks. A substudy of immunological function restoration was performed in 22 patients (LPV/r n=10 and EFV n=12). Activation, thymic function, apoptosis, senescence, exhaustion, Treg cells, IL-7-receptor/IL-7 system, thymic volume and lymphoid tissue fibrosis were evaluated at baseline and at week 48. Results: Both groups experienced CD4+ count increase that was higher in the EFV group (∆CD4+ 88 vs 315 cells/L LPV/r vs EFV, respectively, p<0.001). Despite this difference in CD4+ gain, the change in other immune function parameters was similar in both treatment groups. Most of parameters evaluated tended to normalize after 48 weeks of cART. A significant decrease in levels of activation, senescence, exhaustion and apoptosis on CD4+ and CD8+ T cells (p<0.001 for all), and a significant increase in markers of thymic function, IL-7-receptor and in the levels of central memory CD4+ T cells and naïve subsets of CD8+ T cells (p<0.001 for all) with respect to baseline values was observed without difference between groups. Conclusions: These data support that the differences in CD4+ gain with different cART regimen are not immunologically meaningful and might explain the similar clinical efficacy of these regimens. Key Words: HIV, antiretroviral therapy, immune reconstitution.