Background Diagnosing infection in infants after cardiac surgery with cardiopulmonary bypass remains challenging. We aimed to determine whether procalcitonin discriminates post-cardiopulmonary bypass systemic inflammatory response syndrome from bacterial infection in infants better than C-reactive protein and leukocyte count. Method One hundred and eight infants underwent cardiac surgery with cardiopulmonary bypass. Leukocyte count, C-reactive protein, and procalcitonin were measured on arrival in the intensive care unit as baseline, and repeated on postoperative day 3. Bacterial infection was defined as proven infection with a positive blood or sputum culture. Results Twenty-four infants had proven bacterial infection. Baseline leukocyte counts and C-reactive protein levels did not differ significantly between the 2 groups. On postoperative day 3, C-reactive protein (62 vs. 38.5 mg·L−1, p = 0.01) and procalcitonin levels (6.58 vs. 0.41 ng·mL−1, p < 0.01) were higher in patients with bacterial infection. Leukocyte counts did not differ significantly between the two groups ( p = 0.94). The area under the receiver operating curve for leukocyte count, C-reactive protein, and procalcitonin was 0.49 ( p = 0.94), 0.67 ( p = 0.01), and 0.87 ( p < 0.0010), respectively. The optimal cutoff value of procalcitonin was 2.5 ng·mL−1 (sensitivity 75%, specificity 88%). Conclusion In infants undergoing cardiac surgery with cardiopulmonary bypass, procalcitonin discriminates bacterial infection from post-cardiopulmonary bypass systemic inflammatory response syndrome better than C-reactive protein and leukocyte count.