There are conflicting data regarding the influence of hepatitis C virus (HCV) infection on the immune restoration experienced by HIV-infected patients who receive highly active antiretroviral therapy (HAART). In this multicenter, retrospective, longitudinal study, CD4 restoration was assessed according to HCV status in treatment-naive HIV-infected patients within 3 years of HAART. Only patients with persistent HIV suppression were included. Factors predicting CD4 gains were analyzed with multivariate linear regression. Out of 322 patients included 139 had positive HCV-RNA and 183 were only HIV infected. HCV-HIV-coinfected patients were older, more often ex-intravenous drug users (IVDU), and had less advanced HIV infection. Baseline CD4 count [OR -0.21 [95% CI (-0.34)-(-0.04)]; p = 0.01] and male sex [OR -0.19 [95% CI (-191.12)-(-10.87)]; p = 0.03] predicted smaller increments in absolute CD4 counts, and higher baseline CD4% [OR -0.38 [95% CI (-0.39)-(-0.21)]; p < 0.0001] and older age [OR -0.12 [95% CI (-0.23)-(-0.01)]; p = 0.03] predicted smaller gains in CD4% after 3 years of HAART. A history of IVDU was associated with smaller absolute CD4 count increases at 1 year of therapy [OR -0.20 [95% CI (-128.32)-(-16.24)]; p = 0.01]. Use of nucleoside reverse transcriptase inhibitor (NRTI)-only regimens and of zidovudine as part of the NRTI backbone was associated with smaller and greater gains in CD4%, respectively. HCV replication per se does not impair the CD4 restoration in HIV-infected patients successfully treated with antiretroviral therapy. Lower baseline CD4 counts are the strongest predictors of greater CD4 gains over a 3-year period, while a history of IVDU negatively affects CD4 restoration only early after the initiation of HAART.