Objective To examine the association between maternal cocaine use during pregnancy and physiological measures of regulation, which included heart rate (HR) and respiratory sinus arrhythmia (RSA). Methods Potential mediators and moderators of this association were explored. Participants were 141 mother–infant dyads (77 cocaine exposed and 64 nonexposed) recruited at birth. Average infant HR and RSA was assessed at 4–8 weeks of age during a 15 minute period of sleep. Results Results indicated a dose-dependent effect of prenatal exposure to cocaine on RSA. There was no evidence that fetal growth or other prenatal exposure to substances mediated this association or that fetal growth or maternal age moderated this association. Regression analyses also indicated that birth weight (BW), but not birthlength (BL), head circumference (HC) or other substance use, mediated the association between prenatal exposure to cocaine and heart rate. Conclusions These results suggest that cocaine exposure is associated with physiological regulation at 4–8 weeks of age and highlight the importance of considering level of exposure when assessing infant outcomes.