Prior reports suggest illness acuity and chronic lung disease may be related in part to inadequate adrenal response in preterm infants. We explored the relationship of premature infants' cortisol response (ΔC) to 1-24 ACTH (Cosyntropin, 3.5 μg/kg IV) with illness acuity and duration of supplemental oxygen. Study Design: Infants ≤35 weeks gestation were eligible. Consent was granted to enroll 40 infants born to 31 mothers. 1-24 ACTH stimulation was administered at 36-72 hrs of age. Plasma cortisol levels were obtained prior to 1-24 ACTH stimulation and 60 minutes later. Hyporesponsive ΔC was defined as < 10 μg/dl. Illness severity was computed on Days 1 and 3 using Score for Neonatal Acute Physiology(SNAP)(Richardson et al, Pediatrics, 1993) and Neonatal Therapeutic Intervention Scoring System (NTISS) (Gray et al, Pediatrics, 1992). Other variables included birthweight (BW), gestational age (GA), size for GA (Babson scale), days on O2 (DOO2), and betamethasone exposure. Results: Average GA was 30.1±3.0 wks SD (BW 1449 ± 574 gms). MeanΔC to 1-24 ACTH = 15.2±7.8 μg/dl. SNAP scores on day 1 & 3 were 7±5SD and 3±2SD respectively. NTISS scores on day 1 & 3 were 13±6 and 10±5SD, respectively. Mean DOO2 = 13±22SD.ΔC correlated with duration betamethasone exposure (r=0.42, p=0.008), size for GA (r=0.47, p=0.03), and with SNAP Day 1 score (r=0.32, p=0.04), but did not correlate with GA, BW, SNAP Day 3 score, NTISS scores on days 1 and 3, nor DOO2. 10 infants with ΔC <10 μg/dl compared to 30 infants withΔC ≥ 10μg/dl were smaller for GA (2.5 v. 3.5 on Babson scale, p<0.03) and had shorter exposure to betamethasone (3.7 v. 11.1 days, p<0.01). Higher ΔC in infants with longer betamethasone exposure was not attributable to GA. Infants with ΔC<10 μg/dl did not differ from infants with ΔC ≥ 10 μg/dl in terms of GA, BW, SNAP, NTISS, or DOO2. Conclusion: The distributions of DOO2, SNAP & NTISS scores reflect that the majority of infants were not critically ill, andΔC revealed no strong or consistent correlation with illness severity nor DOO2. Longer betamethasone exposure in infants with ΔC> 10μg/dl suggests that length of antenatal steroid exposure may facilitate induction of HPA axis or enzyme systems for cortisol production. SGA infants may have impaired cortisol response to ACTH.