OBJECTIVE To investigate the combined usefulness of CD4 lymphocyte counts and human immunodeficiency virus type 1 (HIV-1) p24 antigen in predicting progression to the acquired immunodeficiency syndrome (AIDS). METHODS CD4 lymphocyte counts and HIV-1 p24 antigen status were evaluated over a 4-year period in 518 HIV-1-seropositive men enrolled in the Multicenter AIDS Cohort Study in Chicago. RESULTS Twenty-six percent (134 of 518) of the HIV-1-seropositive cohort had detectable p24 antigen during the study period. Men with p24 antigenemia experienced a more rapid decline in CD4 lymphocyte counts than men who were persistently p24 antigen-negative (p less than 0.01). Mean CD4 lymphocyte counts at first detection of p24 antigen were 406 and 455 cells/microL for men with incident and prevalent antigenemia, respectively. Antigen was detected in 61% (63 of 103) of the men who progressed to AIDS and in only 17% (71 of 415) of the men who did not (p less than 0.0001). The 4-year estimated cumulative AIDS incidence was 86%, 63%, and 21% for men with entry CD4 counts less than 200, 200 to 399, and 400 or more cells/microL, respectively. Presence of p24 antigenemia was strongly associated with more rapid disease progression within each of these CD4 groupings (p less than 0.0001). CONCLUSIONS Our data indicate that p24 antigenemia can first be detected with moderate CD4 cell depletion, is associated with a more rapid decline in the CD4 lymphocyte population, and combined with CD4 lymphocyte counts is useful in identifying individuals at significantly greater risk of disease progression. Our findings provide important information for assessing HIV-1 disease prognosis over a 4-year period.