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The CD4+ lymphocyte is a major target of the human immunodeficiency virus type 1 (HIV-1). CD4+ T-lymphocyte measures have been used to predict the risk of HIV-1-related complications in diverse populations, to guide management decisions, and to define cases of the acquired immunodeficiency syndrome (AIDS). To examine the role of CD4+ measures in the management and epidemiologic monitoring of HIV-1 infection, we evaluated current literature regarding the accuracy and precision of CD4+ measures and the use of these and other prognostic measures in the care of HIV-1-infected persons. Several studies have reported wide intraindividual and interindividual variability in the absolute CD4+ count, which can detract from its clinical usefulness. Approaches to address this variability include the following: drawing specimens at a similar time of the day; monitoring CD4+ percent that has less variability; following a meticulous laboratory technique; using serial tests to guide management decisions; and retesting after efforts to eliminate transient treatment and clinical factors that can affect the CD4+ count. The expense and limited availability of CD4+ measures also present barriers to widespread use. Other laboratory and clinical factors offer additional prognostic information and have an evolving role in management decisions. CD4+ measures have an important role in HIV-1 clinical care, research, and disease surveillance, but strategies are required to address problems with variability, expense, and availability.