Tumor necrosis factor-alpha (TNF alpha), a potential regulator of HIV-1 replication, is involved in the progression of AIDS and associated disorders such as muscle wasting, fever and gastrointestinal problems. HIV-seropositive patients were assigned to receive zidovudine (ZDV; 100 mg 4-5 times/d) alone (n = 14), pentoxifylline (PTX; 400 mg every 8 h), a drug known to block TNF alpha release (n = 7), or PTX and ZDV (n = 11) for 12 weeks in a prospective, open-label study. Weekly compliance checks and biweekly blood and 24-h urine samples were obtained for immunological assessments. Baseline TNF alpha levels were elevated in all study patients, independent of disease stage. There were no appreciable differences in immunologic variables (CD4 counts, total and unbound p24 antigen, TNF alpha, beta 2-microglobulin, and urinary neopterin levels) between groups. The mean HIV-1 viral load, as measured by a quantitative polymerase chain reaction technique, was 1.9-fold above baseline values after 12 weeks of ZDV and PTX compared with 8- to 9-fold greater levels in patients given either agent alone (p < 0.05). TNF alpha levels correlated with viral load (r = 0.67; p < 0.0001) in patients given the combined drug regimen. Virological evidence of lack of progression in AIDS patients suggests the beneficial use of ZDV and PTX in delaying progressive HIV-1 disease compared with each drug alone.