Cerebral injury is an important complication after cardiac surgery with the use of cardiopulmonary bypass. The rate of overt stroke after cardiac surgery is 1% to 2%, whereas silent strokes, detected by diffusion-weighted magnetic resonance imaging, are found in up to 50% of patients. It is unclear whether a higher versus a lower blood pressure during cardiopulmonary bypass reduces cerebral infarction in these patients. In a patient- and assessor-blinded randomized trial, we allocated patients to a higher (70-80 mm Hg) or lower (40-50 mm Hg) target for mean arterial pressure by the titration of norepinephrine during cardiopulmonary bypass. Pump flow was fixed at 2.4 L·min ·m . The primary outcome was the total volume of new ischemic cerebral lesions (summed in millimeters cubed), expressed as the difference between diffusion-weighted imaging conducted preoperatively and again postoperatively between days 3 and 6. Secondary outcomes included diffusion-weighted imaging-evaluated total number of new ischemic lesions. Among the 197 enrolled patients, mean (SD) age was 65.0 (10.7) years in the low-target group (n=99) and 69.4 (8.9) years in the high-target group (n=98). Procedural risk scores were comparable between groups. Overall, diffusion-weighted imaging revealed new cerebral lesions in 52.8% of patients in the low-target group versus 55.7% in the high-target group ( =0.76). The primary outcome of volume of new cerebral lesions was comparable between groups, 25 mm (interquartile range, 0-118 mm ; range, 0-25 261 mm ) in the low-target group versus 29 mm (interquartile range, 0-143 mm ; range, 0-22 116 mm ) in the high-target group (median difference estimate, 0; 95% confidence interval, -25 to 0.028; =0.99), as was the secondary outcome of number of new lesions (1 interquartile range, 0-2; range, 0-24 versus 1 interquartile range, 0-2; range, 0-29 respectively; median difference estimate, 0; 95% confidence interval, 0-0; =0.71). No significant difference was observed in frequency of severe adverse events. Among patients undergoing on-pump cardiac surgery, targeting a higher versus a lower mean arterial pressure during cardiopulmonary bypass did not seem to affect the volume or number of new cerebral infarcts. URL: https://www.clinicaltrials.gov. Unique identifier: NCT02185885.