To determine if suppression of human immunodeficiency virus (HIV) replication during anti-retroviral 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 greater-than-or-equal-to 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.