Aspirin prolongs the bleeding time in normal subjects and inhibits platelet release and aggregation with connective tissue and other biological agents. We have investigated one of the possible mechanisms by which aspirin prolongs the bleeding time by comparing the effects of aspirin and placebo on the bleeding time and platelet aggregation with connective tissue in normal volunteers. Two separate studies were performed. Both showed prolongation of the bleeding time and inhibition of the platelet connective tissue reaction after aspirin, but only the second study showed a significant correlation between these changes. Both studies are reported in detail because the discrepancy between them illustrates some important principles that require consideration when relating the effects of drugs on platelet function in vitro to their effects in vivo. The findings suggest that when particular care is taken to standardize the measurement of the platelet connective tissue reaction in terms of the stimulus used, subject variability, and analysis of results, the prolonged bleeding time after aspirin can be shown to be related to the defect produced in the platelet connective tissue reaction.