It has been observed that preterm infants of substance abusing mothers(ISAM) have decreased incidence of respiratory distress syndrome. The mechanism is unclear. In animal and adult studies, cocaine administration increased plasma cortisol levels. (Pediatr Res 1991;29:534-7 and Am J Obstet Gynecol 1991; 164:658-63). However, chronic heroin abuse decreased basal cortisol levels. In very low birth weight (VLBW) infants of substance abusing mothers, data regarding plasma cortisol levels early in life have not been reported. We measured plasma cortisol levels in the first 48 hours of life in 7 VLBW infants of substance abusing mothers (cocaine, heroin). The mean birth weight was 834 g (range 480 to 1175 g). The mean gestational age was 27 weeks. Seven matched VLBW infants without a history of maternal drug abuse served as the control group [mean birth weight 845 g (range 490 to 1285g); mean gestational age 27 weeks]. Cortisol levels were measured by the radioimmunoassay method in all patients. Mean plasma cortisol level in ISAM infants was 65.3 mcg/dl (range 11.9 to 144 mcg/dl) and was significantly higher than in the control group (mean cortisol level 11.6 mcg/dl; range 2.7 to 26.7 mcg/dl) (P = 0.026, two-tailed). Our preliminary data suggest that maternal drug abuse significantly increases plasma cortisol levels in VLBW infants. Further studies are needed to confirm our findings and to correlate cortisol levels in this group of patients with lung maturation.