The use of ibuprofen (IBP) in hemophilic men for chronic hemophilic arthropathy is associated with transient coagulation abnormalities, but usually does not cause bleeding symptoms. However, when hemophilic men are treated with ibuprofen while also receiving zidovudine (ZDV), excess bleeding has occurred in some. In order to evaluate platelet function and pharmacokinetics of combination IBP and ZDV, we measured platelet aggregation, platelet adhesive index, bleeding time, and IBP and ZDV drug levels by high performance liquid chromatography on five patients receiving chronic oral IBP, 400 mg every 6 hr, and on ten patients receiving both IBP and ZDV, 100 or 200 mg every 4 hr five times daily. Samples were obtained at baseline (ZDV alone), acutely (IBP+ZDV acutely), and chronically (2 weeks on IBP and ZDV). Abnormal platelet aggregation with arachidonic acid occurred in four of five (80%) of those receiving IBP alone and in 7 of 10 (70%) at baseline, 9 of 10 (90%) at acute, and 8 of 10 (80%) at chronic IBP and ZDV treatment, most commonly at 2 hr following dosing, when peak IBP levels occurred, and persisting 4 hr in those on chronic dosing. Half or more of those on combination IBP+ZDV showed a lowered platelet adhesive index and/or prolonged bleeding time. Excess bleeding symptoms occurred in three on chronic combination IBP+ZDV, two with increased frequency of spontaneous hemorrhages, and one with prolonged traumatic bleeding. Bleeding tendency was unrelated to the degree of platelet function abnormality, to peak drug levels of IBP or ZDV, or degree of liver function abnormality (SGPT). The clearance of IBP alone and ZDV alone were not different from the clearance of combination IBP and ZDV. Caution is urged regarding potential enhanced bleeding tendency in hemophiliacs receiving both IBP and ZDV in combination.