Although a high prevalence of substance use and its adverse effects on the course of the disease have been reported in adolescents with asthma, no studies have attempted to ameliorate the risk through adequate interventions. This pilot study evaluates and supports the feasibility and the effectiveness of a decision-making program in improving decision-making quality and reducing risk motivation over a 6-month study period. Differential effectiveness of the intervention was observed by race and gender. Although the improvement of decision-making quality was observed only in Whites, changes in risk motivation were detected only in non-Whites and girls. No significant reduction in actual substance use behavior was found. The intervention was favorably received by participants. An approach enhancing decision-making quality can be effective in addressing the risk of substance use in adolescent with asthma by altering motivations.