We assessed the risk of acquired immunodeficiency syndrome (AIDS)-related opportunistic illness or death among persons first prescribed highly active antiretroviral therapy (HAART) in January 1996 or later in the Centers for Disease Control and Prevention's Adult and Adolescent HIV Spectrum of Disease Project. Patients were included if they were naive to antiretroviral drugs and had no history of AIDS-related opportunistic illness. Risk was assessed as a function of CD4+ lymphocyte count and human immunodeficiency virus load at the time of initiation of HAART in a Cox proportional hazards model. Hazard ratios for AIDS or death were 6.3, 3.5, and 1.7 for persons with baseline CD4+ cell counts of 0-49, 50-199, and 200-349 cells/microL, respectively, compared with the referent (CD4+ cell count > or =500 cells/microL). HAART should not be deferred until the CD4+ cell count reaches <200 cells/microL. The increased hazard associated with CD4+ cell counts of 200-349 cells/microL was modest but supports initiation of HAART at CD4+ cell counts <350 cells/microL, particularly in patients with high virus loads.