OBJECTIVE Because infants have relatively more blood loss (mL/kg) than older children during cardiac surgery involving cardiopulmonary bypass (CPB), the authors compared hemostatic activation between infants and older children undergoing cardiac surgery. METHODS Observational study. METHODS University-affiliated children's hospital. METHODS Twenty-eight children (18 infants <1 year and 10 children >1 year) undergoing cardiac surgery with CPB. METHODS None. RESULTS Markers of coagulation and fibrinolysis were evaluated at 9 sample points before, during, and after CPB in the 28 children. Infants had greater chest tube output, longer CPB times, and a larger drop in platelet counts during CPB than children. Active tissue plasminogen activator (tPA) increased during CPB in both groups, with infants showing lower levels than children (p < 0.001). In both groups, active plasminogen activator inhibitor type 1 (PAI-1) first decreased during CPB and then increased above baseline postoperatively. Infants had higher PAI-1 than children near the end of CPB (p = 0.01). Thrombin-antithrombin complex levels increased during and after CPB, with infants showing lower levels only during CPB (p = 0.01). D-dimer and prothrombin activation peptide (F1.2) levels increased in a similar pattern for both groups during and after CPB. The length of aortic cross-clamp time and the level of F1.2 after protamine administration correlated significantly and independently with 12-hour chest tube output. CONCLUSIONS Compared with children, infants had greater blood loss (mL/kg), greater drop in platelets during CPB, lower active tPA, and higher active PAI-1. Cumulative thrombin generation after CPB, indicated by F1.2 levels, correlated with early blood loss.