Background -Cerebral injury is an important complication following cardiac surgery with the use of cardiopulmonary bypass (CPB). The rate of overt stroke after cardiac surgery is 1-2%, whereas silent strokes, detected by diffusion-weighed magnetic resonance imaging (DWI), are found in up to 50% of patients. It is unclear if a higher versus a lower blood pressure during cardiopulmonary bypass reduces cerebral infarction in these patients. Methods -In a patient- and assessor-blinded randomized trial, we allocated patients to a higher (70-80 mmHg) or lower (40-50 mmHg) target for mean arterial pressure by the titration of norepinephrine during cardiopulmonary bypass. Pump flow was fixed at 2.4 L/min/m2. The primary outcome was the total volume of new ischemic cerebral lesions (sum in mm3), expressed as the difference between DWI conducted preoperatively and again postoperatively between day 3 and 6. Secondary outcomes included DWI-evaluated total number of new ischemic lesions. Results -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, DWI revealed new cerebral lesions in 52.8% of patients in the low-target group versus 55.7% in the high-target group (p = 0.76). The primary outcome of volume of new cerebral lesions was comparable between groups, 25 mm3 (interquartile range [IQR], 0-118; range 0-25261) in the low-target group vs 29 mm3 (IQR 0-143; range 0-22116) in the high-target group (median difference estimate, 0 (95% confidence interval [95% CI] -25 - 0.028); P=0.99), as was the secondary outcome of number of new lesions (1 (IQR 0-2; range 0-24) vs 1 (IQR 0-2; range 0-29) respectively; median difference estimate, 0 (95% CI 0 - 0); P=0.71). No significant difference was observed in frequency of severe adverse events. Conclusions -Among patients undergoing on-pump cardiac surgery, targeting a higher versus a lower MAP during cardiopulmonary bypass did not seem to affect the volume or numbers of new cerebral infarcts. Clinical Trial Registration -URL: http://www.clinicaltrials.gov Unique identifier: NCT02185885.