Objectives: A goal for long-term therapy of HIV infection is immune control of virus replication rather than the somewhat unrealistic aim of complete viral elimination. This paper will review the evidence that the control of viral infection can be achieved by an active CD8+ T-cell-mediated response. Design: This review will draw on both experimental and clinical sources to discuss the potential mechanisms of the immune control. Results: Data indicate that HIV infection can be effectively controlled by HIV-specific CD8+ T-cell-mediated responses. In infected individuals, the development of active cytotoxic T lymphocytes (CTLs, as measured by lytic activity) is associated with the control of viral replication. Within the simian immunodeficiency virus infection model in rhesus macaques, strong CTL responses are similarly associated with effective viral control. In addition, depletion by antibodies of CD8+ T cells within infected macaques results in rapid increases in viral load. However, in most HIV-infected individuals, the CDS+ T-cells response is inefficient at low antigen dose, probably due to the lack of an effective H IV-specific CD4+ T-cell response. If this CD4+ T-cell response is lost due to viral induced anergy, rather than clonal deletion, such responses may be generated by interruptions in antiretroviral treatment, and/or therapeutic immunization in chronically infected patients. A strong immune response stimulated at low-antigen dose early during viral rebound may be critical in preventing accumulation of toxic viral products that might inhibit effective CD4+ T-cell responses. Conclusion: Immune control of HIV infection is a realistic goal. Understanding both the basic immune mechanisms of in vivo viral replication and identifying practical therapeutic regimens to activate HIV CD4+ and CD8+ T-cell responses may allow the development of efficient immune control of HIV replication in chronically infected patients. © 2001 Lippincott Williams & Wilkins.