Background: This study examined the association between prenatal cocaine exposure (PCE) and autonomic regulation at 13 months of age. Methods: Measures of respiratory sinus arrhythmia (RSA) were obtained from 156 (79 exposed, and 77 nonexposed) infants during baseline and during tasks designed to elicit positive (PA) and negative affect (NA). Results: There was a significant suppression of RSA during the negative affect task for nonexposed infants but not for exposed infants. Maternal symptoms of depression or anxiety (MDA) did not mediate this association. However, gender and MDA did moderate this association such that exposed boys and exposed infants whose mothers had higher levels of MDA had an increase in RSA during a task designed to elicit NA rather than the typical pattern of RSA suppression. Conclusions: These results suggest that there are several possible pathways from PCE to physiological dysregulation during late infancy.