Background: We assessed trajectories of children's internalizing symptoms as predicted by interactions among maternal internalizing symptoms, respiratory sinus arrhythmia (RSA) and child sex. Method: An ethnically and socioeconomically diverse sample of children (n = 251) participated during three study waves. Children's mean ages were 8.23 years (SD = 0.72) at T1, 9.31 years (SD = 0.79) at T2 and 10.28 years (SD = 0.99) at T3. Results: Multiple-indicator multilevel latent growth analyses showed maternal internalizing symptoms interacted with child RSA and sex to predict children's internalizing symptoms. Girls with higher RSA whose mothers had lower levels of internalizing symptoms showed the steepest decline in internalizing symptoms across time. Girls with lower RSA whose mothers had higher levels of internalizing symptoms showed the highest levels of internalizing symptoms at T3, whereas boys with higher RSA whose mothers had higher levels of internalizing symptoms showed the highest levels of internalizing symptoms at T3. Conclusions: Findings build on this scant literature and support the importance of individual differences in children's physiological regulation in the prediction of psychopathology otherwise associated with familial risk.