Maternal mental health and prenatal stress are linked with neurobehavioral differences in the offspring. The majority of studies documenting this effect have been conducted using either predominantly European American infants or minority infants exposed to teratogens in utero. In this study, we focus on healthy African American women from low-income environments to investigate the earliest individual differences in biobehavioral regulation, including resting heart rate and variability (HRV). In 87 neonates, HRV was significantly lower in those born to mothers reporting past major depressive disorder (p = .01). The number of maternal life stressors also was associated with lower neonatal HRV (p = .03). Obstetrical complications were not associated with significant differences, but breast- versus bottle-feeding in the first few days of life was related to higher HRV (p = .04). Early variation in physiological regulation may be linked to subsequent individual differences in response to stress. Thus, identifying the earliest point in development when such differences can be reliably measured may result in opportunities for prevention of later deficits in regulating response to stress.