Residual platelet reactivity (RPR) following coronary artery bypass grafting (CABG) might be related to thrombotic complications and major ischemic cardiac events. The aim of this study was to evaluate the changes in platelet reactivity monitored pre- and postoperatively using multiple-electrode aggregometry (MEA) and to propose an alternative therapeutic approach in a subgroup of patients with postoperative RPR. Ninety-nine patients undergoing elective CABG were enrolled in the study, of whom 41 (41.4%) were diabetic. Preoperatively, all patients received 100 mg acetylsalicylic acid (ASA), with 47 of 99 (47.4%) patients receiving an additional 75 mg clopidogrel (CLO). The blood samples were drawn the day before surgery, and on the first and 4th postoperative day. Platelet count and fibrinogen level were documented, as well as type and daily dose of antiplatelet therapy (APT) received pre- and postoperatively. Multiple-electrode aggregometry using tests based on arachidonic acid (ASPI test) and adenosine diphosphate (ADP test) was performed on the day before and 4 days after surgery. Preoperatively, we detected 31 of 99 (31.3%) patients with RPR (ASPI > 30 AUC). Platelet count correlated with both the ASPI (P = 0.03) and ADP (0.002) tests. Fibrinogen correlated with ADP test values (P < 0.001) and was found to have a higher level in the diabetic subgroup (P = 0.01). In comparison with preoperative results, we detected higher values of ASPI test postoperatively (P = 0.04), with 46 of 99 (46.5%) patients having RPR despite a higher dose of 300 mg ASA being administered. Postoperatively, diabetic patients had higher ASPI test values (P = 0.01), and a higher proportion of patients with RPR compared with the nondiabetic subgroup (58.5 vs 38%, P = 0.04). The subgroup of patients with detected ASPI >30 AUC at the 4th postoperative day consequently received as a part of our clinical routine an additional 75 mg CLO per day, in terms of platelet inhibition optimization. Multiple-electrode aggregometry can recognize patients with RPR during both the pre- and post-CABG period. Postoperatively administered ASA (300 mg) did not sufficiently inhibit platelet aggregation in 46.5% of post-CABG patients. In this group of patients a switch to dual APT should be considered.