Whether and to what extent gut mucosal CD4(+) T cells of HIV-infected patients can be restored by combination antiretroviral therapy (cART) is not yet fully resolved. We studied absolute numbers, differentiation, and activation of mucosal CD4(+) T cells at different stages of HIV infection and assessed the effect of timing of cART initiation on this cell population. Mucosal CD4(+) T-cell numbers were severely reduced at all stages of chronic infection, but normal in patients with acute infection. In patients with initiation of cART during chronic HIV infection, mucosal CD4(+) T cells restored to less than half of the numbers in controls. However, in patients who initiated cART during acute HIV infection, mucosal CD4(+) T-cell numbers were fully preserved and markers of microbial translocation and inflammation reversed to normal. The proportion of mucosal effector memory CD4(+) T cells normalized only if cART was initiated at >350 CD4(+) T cells per μl blood but not with delayed treatment. In conclusion, mucosal CD4(+) T-cell numbers can be preserved if cART is initiated in acute HIV infection. In chronically HIV-infected patients, early cART improves mucosal CD4(+) T-cell differentiation but cannot prevent the persistent lack of total CD4(+) T cells.