Background: Adequate adrenocortical function is essential for survival of critically ill neonates. Although most of them display elevated plasma cortisol concentrations, which reflects activation of the hypothalamic pituitary adrenal axis (HPA), yet; adrenocortical insufficiency is seen in septic shock. Objectives: Evaluate the HPA response in critically ill neonates with shock. Subjects:this prospective observational study included a total of 60 neonates divided into 3 groups;(A)30 critical ill neonates with septic shock on inotropic support, (B)15 patients with sepsis who did not need inotropic support and(C) control group(n=15). Methods: Adrenal functions were evaluated by taking a single diurnal ACTH reading and two readings for serum cortisol level (diurnal and nocturnal). Results: Gram negative organism was more prevalent among the patients; 53%, 63% in groups A and B respectively. Group A showed Significant statistical hypotension before vasopressor drug administration (p<0.001) as compared to both groups. Group A showed Significant statistical improvement of blood pressure after vasopressor drug administration (p<0.001) as compared to both groups B, C. Serum cortisol was significantly higher in group A(57.21 plus-or-minus sign 24.31) and B (48.01 plus-or-minus sign 18.27 ), while it was lower in group C(19.57plus-or-minus sign 16.05 ) . A highly statistically significant rise of serum cortisol level( p=0.000) and ACTH(p=0.000) in group A when was compared to the other two groupsConclusion: This study introduced a new pattern of serum cortisol response in neonates ranging from very high cortisol level to a near normal values; highlighting a state of glucocorticoid resistance in neonates and relative adrenal insufficiency.