Blood priming is needed for cardiopulmonary bypass (CPB) in neonates and infants to avoid exceeding hemodilution; however, transfusion‐related inflammation affects post‐CPB outcomes in infant open‐heart surgery. Procalcitonin, a newly detected inflammatory moderator and a sensitive parameter for predicting pulmonary dysfunction secondary to CPB, rises after CPB. We hypothesized that the hemofiltration of priming blood before CPB might decrease inflammatory mediators in the blood and post‐CPB inflammatory replications, thereby improving the respiratory function after CPB in infants. Sixty infants with a weight below 10 kg were divided randomly into two equal groups of CPB with the zero‐balance ultrafiltration (Z‐BUF) of priming blood and CPB without it. The procalcitonin level was measured before anesthesia, after admission to the intensive care unit (ICU), and 24 h afterward. The respiratory index and pulmonary compliance were measured after anesthesia, at the end of CPB, and 2 h after admission to the ICU. Additionally, time to extubation was recorded. The Z‐BUF of priming blood maintained electrolytes within a physiologic level, and procalcitonin had a slighter rise in the Z‐BUF Group at 24 h after admission to the ICU (P = 0.05). The respiratory index was decreased in the Z‐BUF Group, but the difference with the control group did not reach statistical significance (P > 0.05). The change in pulmonary compliance was significantly increased in the cyanotic patients in the intervention group, but there was no significant difference between the two groups. The time to extubation and the ICU stay were shorter in the Z‐BUF Group (P < 0.05). A positive correlation was found between the peak procalcitonin concentration and the time to extubation directly and pulmonary compliance reversely. These results suggest that the Z‐BUF of priming blood may have some beneficial clinical effects such as improved respiratory function and attenuated procalcitonin.