Background: Depressed mood and Substance misuse are prevalent during adolescence, but rates differ between males and females. Little is known regarding how depressed mood influences response to substance use interventions and interacts with gender in connection with subsequent drinking. This study explores the relationship of depressed mood and gender to treatment response in adolescents admitted to an Emergency Department (ED). for alcohol-related incidents. Methods: Adolescents treated at an ED were randomly assigned to a Motivational Interviewing condition or to standard hospital care. Participants (N = 268; ages 13 to 19) were followed for 6 months with detailed measures of alcohol involvement and depressed mood. Results: Depressed mood at the time of the ED visit predicted less drinking at 6-month follow-up for 13- to 17-year-old girls, but predicted more follow-up drinking for 13- to 17-year-old boys and for 18- to 19-year-old females, above and beyond effects of baseline drinking. Depressed mood did not moderate the relationship between treatment condition and drinking outcome. Conclusions: Depressed mood as reported at the time of an ED visit appears to motivate drinking reductions in early- to mid-adolescent girls. Depressive symptoms may indicate an adaptive distress response to the event that precipitated the ED visit, which clinicians could capitalize on by heightening awareness of adverse risks and collaborating to set goals. In contrast, depression may be a liability in teenage boys and older teenage girls, and mood symptoms could be an additional target for intervention.