This study examined the effects of prematurity, cumulative medical risk, and proximal and distal social forces on individual differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis in young adulthood. A prospective sample of 149 infants born healthy preterm (PT; n = 22), sick PT ( n = 93, medical illness, neurological illness, small for gestational age), and full term ( n = 34) was recruited from a Level III neonatal intensive care unit in southern New England between 1985 and 1989 and followed to age 23 years. Cumulative medical risk was indexed across seven assessment waves (spanning 17 years) using medical and neurological health status at birth, toddlerhood (ages 18 and 30 months), childhood (ages 4 and 8 years), and adolescence (ages 12 and 17 years). Distal risk included socioeconomic status (SES) at birth. Proximal social factors were indexed from assessments of the home environment and measures of child vulnerability and maternal self-esteem, involvement, and control style from birth, 4 years, 8 years, and 12 years. At age 23 years, five saliva samples were collected upon awakening, 45 min after waking, 4 hr after waking, 8 hr after waking, and bedtime (later assayed for cortisol). Results reveal effects of cumulative medical risk on the diurnal pattern of HPA axis activity, with moderating effects of SES and proximal social factors. Findings are discussed in terms of implications for contemporary theories related to developmental sensitivity and susceptibility to context and the developmental origins of health and disease theory.