Objectives: Reduction of cognitive function is a possible side effect after coronary artery surgery using cardiopulmonary bypass (CPB). We investigated the effect of single versus dual antiplatelet therapy on cognitive performance in patients undergoing coronary artery bypass grafting (CABG) with CPB. Methods: 50 consecutive CABG patients with preoperative intake of aspirin were compared to 49 consecutive patients with aspirin and clopidogrel. Six neuropsychological subtests from the Syndrom Kurz Test and the Alzheimer's Disease Assessment Scale were performed preoperatively and on the third postoperative day. To assess the overall cognitive function and the degree of cognitive decline across all tests after surgery we combined the six test-scores by principal component analysis. Results: Patients had a mean age of 66.1 ± 9.3 years, received a mean of 2.8 ± 1.0 bypasses within an average of 87 ± 31 minutes on cardiopulmonary bypass. These parameters as well as the preoperative combined neurocognitive score were not significantly different between the groups. After the operation there was a significant deterioration of the combined neuropsychological score in both groups (single: preop −0.2 ± 1.5 vs. postop −1.8 ± 1.7, p = 0.000 and dual: preop 0.2 ± 1.5 vs. postop −0.5 ± 2.1, p = 0.004). However, the patients operated under dual antiplatelet therapy showed a significant less decline of overall cognitive function compared to the single antiplatelet therapy patients (dual: 0.7 ± 1.5 vs single: 1.6 ± 1.6, p = 0.004). Conclusion: Dual antiplatelet therapy has a cerebroprotective effect in patients undergoing coronary artery bypass surgery. Compared to single antiplatelet therapy it reduces an early postoperative substantial decline of neuropsychological abilities.