Purpose: Low-dose ASA (81 mg daily) is administered after coronary artery bypass graft (CABG) surgery to reduce the risk of graft failure. There is transient ASA resistance after such surgery, which may compromise its effectiveness. Because such resistance may reflect the failure of once-daily, low-dose ASA to acetylate cyclo-oxygenase (COX)-1 and inhibit thomboxane A2 (TXA2) synthesis in the setting of the increased platelet turnover that occurs post-operatively, we performed a randomized trial to determine whether higher-dose once-daily or more frequent ASA dosing overcomes the resistance observed with usual ASA dosing. Methods: Adults undergoing CABG surgery were randomized to one of 3 ASA dosing regimens; 81 mg once-daily, 325 mg once-daily, or 81mg four times daily. ASA was started on the first post-operative day and continued until day 7 or hospital discharge. Using an immunoassay, levels of serum TXB2, the stable metabolite of TXA2, were measured daily before starting ASA. The primary outcome was the median TXB2 level on postoperative day 4. Results: A total of 100 patients undergoing CABG surgery (mean age 65, females 16%) were randomized. On day 4, median TXB2 level in the group receiving ASA 81mg once-daily was 10.7 ng/ml (Q1,Q3; 6.1,30.8 ng/ml). The median TXB2 levels were significantly lower in the groups randomized to ASA 325 mg once-daily and 81 mg four times daily; 3.6 ng/ml (Q1,Q3; 1.9,10.1 ng/ml) and 1.1 ng/ml (Q1,Q3; 0.5,2.4 ng/ml), respectively; P=0.001 and P<0.0001, respectively. Conclusions: ASA resistance after CABG surgery, defined as failure of ASA to suppress TXB2 formation, is attenuated by higher dose once-daily ASA and almost abolished by four times daily low-dose ASA. The efficacy of more frequent ASA dosing supports the concept that resistance reflects, at least in part, increased platelet turnover. Attenuation of TXB2 production by higher dose once-daily ASA raises the possibility that the susceptibility of megakaryocyte COX-1 to acetylation by ASA may be dose-dependent.