Background: Despite findings that parent depression increases children's risk for internalizing and externalizing problems, little is known about other factors that combine with parent depression to contribute to behavior problems. Methods: As part of a longitudinal, interdisciplinary study on childhood-onset depression (COD), we examined the association of mother history of COD, child frontal electroencephalogram asymmetry, and affective behavior with children's concurrent behavior problems. Results: Children in the COD group had higher anxious/depressed and aggressive problems than did children in the control group, but this was qualified by a COD-by-asymmetry interaction effect. For COD but not control children, left frontal asymmetry was associated with both anxious/depressed and aggressive child problems. Children with left frontal asymmetry and low affect regulation behavior had higher anxious/depressed problems than did those with high affect regulation behavior. Boys with left frontal asymmetry had higher aggressive problems than did those with right frontal asymmetry. Conclusions: In children of mothers with COD, physiological and behavioral indices of affect regulation may constitute risks for behavior problems.