To determine if suppression of human immunodeficiency virus (HIV) replication during antiretroviral therapy correlates with clinical outcome, serial quantitative serum cultures and HIV p24 antigen measurements were made in patients with advanced HIV disease treated with didanosine. Twenty-one (78%) of 27 had viremia detected, and in 14 (67%) viral titer decreased by fivefold or more. Compared with those with no decrease, patients who had a decrease in titer were more likely to achieve a > or = 5% increase in body weight (8/12 vs. 0/7, P = .013) and had a significantly greater mean increase in body weight during treatment months 1-5. Occurrence of new AIDS-defining illnesses and survival were not significantly different between groups. Changes in p24 antigenemia did not correlate with any parameter of clinical outcome examined. Changing serum HIV titer is a marker of the virologic effect of didanosine therapy that correlates with the early clinical benefit as reflected by weight gain. However, correlation of this marker with long-term clinical benefit is uncertain.