Conventional coagulation tests might be inadequate to explore mechanisms regulating thrombin generation in neonates, because they do not allow full activation of the reduced levels of protein C. Therefore, they do not reflect the action of pro- and anti-coagulants as does the endogenous thrombin potential assessed in the presence of thrombomodulin. Endogenous thrombin potential measured without thrombomodulin was greater than the lower-limit of the adult reference interval in 30% of 109 full-term and 49% of 55 pre-term neonates, a finding consistent with the reduced levels of procoagulants in this setting. When the test was modified adding thrombomodulin, endogenous thrombin potential reverted into the adult reference interval in 97% and 100% full-term and pre-term neonates. In conclusion, the coagulation balance in neonates is restored by the concomitant reduction of pro- and anticoagulants. The restored balance can be shown in vitro by the endogenous thrombin potential test that includes thrombomodulin, but not by conventional coagulation tests.