In 79 homosexual men infected with human immunodeficiency virus (HIV), urinary neopterin was significantly higher as compared with 70 HIV-seronegative men in the same cohort (p < 0.0001). This highly significant association was found both for naturally occurring oxidized (native) neopterin and for total neopterin (native plus chemically oxidized forms). In prospective follow-up for 18 months, the odds that the acquired immune deficiency syndrome (AIDS) would develop were elevated 25-fold among those whose native neopterin levels were in the highest quartile compared with those with lower neopterin levels, and the corresponding odds ratio for total neopterin was 7.8. Logistic regression analyses indicated that neopterin added useful information to T4-cell count in predicting AIDS onset and that both are statistically significant in the multivariate model. A cross-sectional survey revealed that neopterin levels were correlated with number of receptive anal intercourse partners in the year before HIV seroconversion (r = 0.60, p = 0.0005). Since neopterin may serve as a marker of monocyte/macrophage activation by soluble factors such as [gamma]-interferon, these data support a growing body of virologic and immunologic evidence that highlights the important role of the monocyte/macrophage in the pathogenesis of AIDS.