P rimary HIV-1 infection causes extensive immune activation, during which CD4⁺ T cell activation supports massive HIV-1 production. We tested the safety and the immune-modulating effects of combining cyclosporin A (CsA) treatment with highly active antiretroviral therapy (HAART) during primary HIV-1 infection. Nine adults with primary HIV-1 infection were treated with CsA along with HAART. At week 8, all patients discontinued CsA but maintained HAART. Viral replication was suppressed to a comparable extent in the CsA + HAART cohort and in 29 control patients whose primary infection was treated with HAART alone. CsA restored normal CD4⁺ T cell levels, both in terms of percentage and absolute numbers. The increase in CD4⁺ T cells was apparent within a week and persisted throughout the study period. CsA was not detrimental to virus-specific CD8⁺ or CD4⁺ T cell responses. At week 48, the proportion of IFN-γ–secreting CD4⁺ and CD4⁺CCR7^– T cells was significantly higher in the CsA + HAART cohort than in the HAART-alone cohort. In conclusion, rapid shutdown of T cell activation in the early phases of primary HIV-1 infection can have long-term beneficial effects and establish a more favorable immunologic set-point. Appropriate, immune-based therapeutic interventions may represent a valuable complement to HAART for treating HIV infection.