This study estimated the impact of gender on the familial associations between attention-deficit/hyperactivity disorder (ADHD) and major depression (MD). The risk for ADHD and MD in first degree relatives was stratified by the presence of MD in boy and girl ADHD probands. In families ascertained via boy probands, the risk for MD was greater in the relatives of both the depressed ADHD and nondepressed ADHD probands. In families ascertained via girl probands, there was cosegregation and the risk of MD was greater only for those relatives of depressed ADHD probands. The results indicate that there may be two mechanisms underlying MD in ADHD families: 1) an etiologically distinct familial subtype of ADHD and MD that is more evident in females, and 2) a familial, gender-specific susceptibility to nonfamilial risk factors that mediate the onset of either ADHD or MD in males and females.