We have recently reported that the Gl toxicity of aspirin is markedly reduced when the drug is preassociated with the zwitterionic phospholipid dipalmitoylphosphatidycholine (DPPC) before intragastric administration. The present study was designed to determine whether the biological availability and therapeutic activity of aspirin were affected by chemically associating the drug with DPPC. To evaluate this, we compared the kinetics of entry of labeled aspirin into the blood, after intragastric administration of the drug in the free and lipid-associated states; we also tested the ability of the above formulations to inhibit fever, inflammation and pain in appropriate rodent model systems. We found that although the Gl absorption of free aspirin and that of the aspirin/DPPC complex were similar, in all three rodent models the complex had significantly greater antipyretic, anti-inflammatory and analgesic efficacy than aspirin alone. Dose-response analyses employing the fever model demonstrated that potency of aspirin to reduce fever was increased 5 to 10-fold when the aspirin was intragastrically administered in the lipid-associated state. We conclude that the therapeutic activity of aspirin to inhibit fever, inflammation and pain is remarkably enhanced when the drug is intragastrically administered in chemical association with the zwitterionic phospholipid DPPC. A number of molecular mechanisms have been proposed to explain the observed phospholipid-dependent increase in aspirin's therapeutic activity.