Background The impact of the coronary artery bypass grafting ( CABG ) technique (on‐ versus off‐pump, single versus multiple aortic clamping) on postoperative neurological outcome remains a matter of controversy. The aim of this study was to assess the association between the incidence of postoperative stroke and the degree of aortic manipulation in one of the largest contemporary CABG series. Methods and Results A retrospective, multicenter, international study was conducted in 25 388 patients undergoing isolated CABG procedures with on‐pump CABG ( ONCAB ) or off‐pump CABG ( OPCAB ) technique including single or multiple aortic clamping. Postoperative stroke was defined as a postoperative neurological deficit lasting more than 24 hours and associated with evidence of a brain lesion on computed tomography. The degree of aortic manipulation was assumed to be higher for on‐pump versus off‐pump surgery and for multiple versus single or no aortic clamping. Logistic regression and propensity matching were used. ONCAB procedures were performed in 17 231 cases and OPCAB in 8157. The incidence of postoperative stroke was significantly lower in the OPCAB group even after propensity matching (0.4% OPCAB versus 1.2% ONCAB , P =0.02). In the ONCAB group (but not in the OPCAB arm) the use of single aortic clamping was associated with significantly reduced postoperative stroke rate (odds ratio, 0.05; 95% CI , 0.008 to 0.07 [ P <0.001]). Conclusions OPCAB and the use of single aortic clamping in the ONCAB arm were associated with a reduced incidence of postoperative stroke. Our data confirm a strong association between aortic manipulation and neurological outcome after CABG surgery.