Recent dramatic decreases in acquired immunodeficiency syndrome-related mortality are largely due to the introduction of highly active antiretroviral therapy (HAART). Although immune restoration due to suppression of human immunodeficiency virus (HIV) replication is a critical determinant of these trends, the magnitude of immune restoration seen after treatment with HAART varies substantially among treated persons and is generally incomplete. Nonetheless, even partial immune restoration is sufficient to provide protection from most major opportunistic infections; these risks can be largely predicted by the number of circulating CD4 cells. Limited data suggest that treatment earlier during the course of HIV infection may result in greater preservation of immune function, though this has not been studied in great detail. Preliminary studies performed among persons with multidrug-resistant virus whose treatment regimens are failing suggest that there is likely a benefit to continuation of therapy that may be related to diminished pathogenicity of drug-resistant virus. As deaths related to opportunistic infections diminish, the spectrum of causes of mortality in HIV infection is changing. Except for Kaposi sarcoma, there is insufficient information to conclude that the risks of non-Hodgkin lymphoma and other malignancies are diminishing among persons with HIV infection. How much immune restoration will be enough to ensure long-term survival in persons with HIV infection remains an open question. JAMA. 2000;284:223-228