Cardiopulmonary bypass (CPB) reduces coagulation factor levels through hemodilution and consumption. Differences in CPB-induced alterations of factor XIII (FXIII) levels in children with cyanotic and acyanotic congenital heart defects (CHDs) are not well characterized. FXIII activity (determined by Berichrom assay), prothrombin index, activated partial thromboplastin time, and fibrinogen were measured before open heart surgery with CPB and 5 days postoperatively for children older than 3 years with acyanotic (n = 30) and cyanotic (n = 30) CHDs. The preoperative FXIII levels did not differ significantly among the children of the compared groups. The cyanotic patients showed a significantly longer duration of CPB (111.4 ± 45.8 vs 71.5 ± 33.6 min; p = 0.026) and aortic cross-clamp (68.0 ± 27.1 vs 45.4 ± 31.4 min; p = 0.034). The drop in FXIII levels after termination of CPB was more profound for the children with cyanotic CHDs (87.1 ± 13.4 to 49.1 ± 13.2 vs 81.5 ± 12.6 to 58.6 ± 11.1 %, respectively; p = 0.018). The cyanotc patients also were restored to their baseline FXIII levels later than the children with acyanotic CHDs (at 48 vs 24 h). The post-CPB dynamics of the majority of the other coagulation parameters in the compared groups of patients were similar. The cyanotic patients experienced significantly greater postoperative blood loss than the acyanotic patients (12.6 ± 4.9 vs 5.0 ± 2.1 mL/kg; p < 0.001) and were transfused with larger volumes of red blood cells (10.4 ± 6.5 vs 4.2 ± 2.5 mL/kg; p = 0.007). The decrease in FXIII levels after CPB is more profound and lasts longer in children with cyanotic CHDs than in acyanotic patients. The rational strategy of postoperative FXIII replacement therapy for these categories of patients needs to be determined.