Aspirin inhibits platelet cyclooxygenase and prevents thromboxane A2 (TXA2) production. Although it is an effective antithrombotic, even at a low doses aspirin may induce gastrointestinal toxicity. We examined the feasibility of delivering aspirin transdermally using two patch systems, one without (type A) and one with (type B) the permeation enhancer limonene. Daily application of two type A patches that had a total surface area of 100 cm2 and contained 84 mg/patch resulted in 85% +/- 6% reduction in serum TXB2 in six male subjects by day 14. Suppression of serum TXB2 was less marked in females (32% +/- 16%). Analysis of the residual drug in the patch showed that each patch delivered 18 +/- 3 mg on day 1 and 17 +/- 4 mg on day 14, with no difference between males and females. Daily application of a single patch B that had a surface area of 50 cm2 and contained 120 mg aspirin resulted in 60% +/- 11% suppression of serum TXB2 by day 14 in nine male subjects and 84% +/- 9% suppression by day 21. Analysis of the applied patches showed that patch B delivered 33 +/- 3 mg of aspirin daily. Plasma aspirin and salicylate were determined by gas chromatography, mass spectrometry. No aspirin was detected, whereas plasma salicylate was 157 +/- 38 ng/ml and 133 +/- 20 ng/ml by day 14 with patch A and patch B, respectively. Analysis of aspirin applied by patch to the skin in three subjects showed marked hydrolysis to the inactive product, salicylic acid. Aspirin can be delivered transdermally by patch in a dose that suppresses platelet cyclooxygenase. The delivery rate is low reflecting hydrolysis of the drug in the skin. Delivery is improved by the permeation enhancer limonene. This novel route of delivery may be applicable to other antithrombotics and may limit the risk of gastrointestinal toxicity.