Objective: To assess the significance of tissue factor pathway inhibitor (TFPI) and thrombin anti-thrombin complex (TATc) as markers of the imbalance between coagulation and fibrinolysis systems in infants with sepsis, respiratory distress as well as infants exposed to peri-natal asphyxia. Method: Forty-five neonates were included and divided into three groups: -fifteen neonates suffering from sepsis, Fifteen neonates suffering from perinatal asphyxia and fifteen neonates suffering from RDS and Compared to ten healthy neonates as control group. All neonates were subjected to detailed perinatal history, full clinical examination, Silverman scoring system for neonates with RDS, imaging procedures (chest x-ray for cases of RDS, cranial ultra-sound and /or brain CT for cases of perinatal asphyxia), CBC with differential white cell count, CRP blood culture for cases of sepsis, TFPI and TATc.Results: In this study, we found that, plasma level of TATc and TFPI were significantly elevated in the three studied groups, when compared to the control group, yet showed non-significant correlation on comparing survivors versus non-survivors. In infants with sepsis both TFPI and TATc showed higher level in Gram negative septic infants compared to Gram positive septic infants. TFPI was positively correlated to I/T ratio and negatively correlated to sepsis score, at the same time TATc showed negative correlation to both sepsis score and I/T ratio.In infants with RDS TFPI was positively correlated to both Silverman scoring system and chest x-ray grading, on the other hand TATc was negatively correlated to both of them.In infants exposed to peri-natal asphyxia TFPI was positively correlated to Apgar score at one and five minutes and negatively correlated to HIE grading, on the other hand TATc was negatively correlated to HIE grading and Apgar score at one minutes and positively correlated to Apgar score at five minutes. Conclusion: The present study demonstrated that activation of both coagulation and fibrinolysis systems were evident in neonates with sepsis, RDS, as well as neonates exposed to perinatal asphyxia as manifested by rise in the level of plasma TFPI and TATc.It could be speculated that measuring of plasma TFPI and TATc concentration might be early and useful indicators of the imbalance of both coagulation and fibrinolysis systems in critically ill neonates.Thus preventive administration of low doses of anti-coagulants might be desirable in neonates with these diseases in order to guard against its fatal complications.