Levels of a 90-kDa protein (90K), recently reported as a possible marker of HIV-1 infection, were serially examined in a group of HIV-1-infected (HIV-1+) and uninfected (HIV-1-) subjects drawn from the same cohort of homosexual men. The first phase of the study included 61 HIV-1+ AIDS-free subjects 4 years (+/- 6 months) postseroconversion and 75 contemporaneous unifected subjects. Two years later, a subset of 35 HIV-1+ AIDS-free subjects and 72 HIV-1- controls was examined. Mean 90K levels for HIV-1+ subjects were significantly higher than for contemporaneous HIV-1- subjects both 4 and 6 years postseroconversion (p < 0.0001). A significantly more rapid progression to AIDS was seen in HIV-1+ subjects with high 90K levels both 4 years (p = 0.01) and 6 years (p = 0.003) postseroconversion. Four years postseroconversion, 90K was significantly correlated with CD8 cell percent, interferon, neopterin, and beta 2-microglobulin (p < 0.05). Two years later, significant correlations were seen between 90K levels and CD4 cell percent, CD4 cell number, and beta 2-microglobulin (p < 0.05). Stepwise-stepdown regression modeling using 90K, CD4 cell percent, interferon, and beta 2-microglobulin levels 4 years postseroconversion showed that the predictive value of a trivariate model of 90K-interferon-CD4 percent was better than any univariate or bivariate model. We conclude that the 90K protein may be a useful predictor of progression to AIDS in HIV-1+ patients, particularly in combination with the established markers of CD4 cell percent and interferon.