The linear return of platelet malondialdhyde (MDA) production after aspirin ingestion as described by Stuart et al.⁴ has been widely accepted as a nonisotopic method for the determination of platelet survival. However, using assays for platelet prostaglandin production and cyclooxygenase activity, a number of authors2, 9, 10, 11 have now reported a 24 to 48-hr delay in recovery after aspirin. This delay has been interpreted as evidence that aspirin inhibits megakaryocyte as well as platelet cyclooxygenase. The discrepancy in these findings has not been explained. We have measured the return of production of MDA and thromboxane B2 (TXB2) by platelets of normal volunteers after a single dose of aspirin using a variety of assay conditions. We find striking differences in the pattern of recovery depending upon the presence of protein in the medium in which the platelets are stimulated. Production of both MDA and TXB2 returns in a linear fashion with time when platelets are washed, resuspended in buffer and stimulated with either NEM or thrombin. A 48-hr lag in recovery is seen when platelets are stimulated in whole blood or platelet-rich plasma, or when washed platelets are resuspended in either platelet-poor plasma or in buffer containing 4 g % albumin. This lag is present regardless of stimulus or metabolite measured. It does not appear to be an artifact resulting from binding of the arachidonic acid or its metabolic products to the protein in the medium, as we are able to detect TXB2 production by even small numbers of aspirin-free platelets in whole blood mixtures. Therefore, if megakaryocyte cyclooxygenase is inhibited by aspirin, this effect is obscured when the platelets are suspended in protein-free medium. We have also studied a number of patients with short platelet survivals as judged by Cr⁵¹ labeling. Survivals using the aspirin method and washed platelets in these patients are consistently longer than those determined simultaneously by Cr⁵¹. This leads us to postulate that there is a lag effect even in the washed platelet system, and that this effect is more evident in states of increased platelet turnover. This complex effect must be better understood before aspirin platelet survivals can be accurately interpreted.