Objective: Despite evidence that impaired reward- and risk-related behavior during adolescence can have potentially serious short- and long-term consequences, few studies have investigated the impact of depression on reward-related selection in adolescents. This study examined the relationship between reward-related behavior and prefrontal activations in depressed and healthy adolescents during a decision-making task. Method: A total of 22 adolescents with no personal or family history of psychiatric illness and 22 adolescents with major depressive disorder were administered a monetary, two-option decision-making task, the Wheel of Fortune, using a functional magnetic resonance imaging protocol. The analysis was focused on the selection phase, i.e., the first phase of the decision-making process, which typically includes two more phases, the anticipation of outcome and the feedback. Results: Similar prefrontal regions were activated in healthy and depressed adolescents during reward-related selection. However, in a contrast involving the selection of high-risk (low-probability/high-magnitude reward) versus equal-risk (50% chance of reward) options, healthy adolescents showed greater activation than patients in the right lateral orbitofrontal cortex (OFC), whereas participants with depression showed greater activation than healthy subjects in the left dorsal OFC and right caudal anterior cingulate cortex. In addition, healthy adolescents, but not participants with depression, showed a negative correlation between high-risk behavior and neuronal activation in prespecified prefrontal regions. Conclusions: These results suggest subtle changes in the neural responses to reward selection in depressed adolescents. These findings should be replicated in larger samples, and the association of these neuronal changes with treatment response and prognosis should be examined. (Contains 4 figures and 2 tables.)