Objective: This study assessed the initial acceptability of SafeUse, a game-based opioid misuse prevention intervention for delivery via smartphone among adolescents. Evidence-based educational and refusal skills training materials were adapted, and game design elements were applied to clinically and scientifically informed scenarios in which opioids are typically introduced to adolescents using standard product development methods to create the SafeUse prototype.Materials and Methods: In a mixed-methods study, 14 adolescents were assessed on their knowledge and perceptions of opioids before and following 5-7 days of access to SafeUse. Participants provided feedback in focus groups on the acceptability, relevance, and understandability of SafeUse and made suggestions for its improvement. Feedback was coded and summarized as to playability, acceptability, appropriateness, content development, and knowledge transfer. Pre- and post-access quantitative data were analyzed using Wilcoxon matched pairs signed-rank tests.Results: Overall, participants liked SafeUse, its characters, graphics, and approach, finding it more appealing than lectures/reading materials and appropriate for school settings. They moderately to extremely liked the game, would like to play more game modules, liked playing through the decisions, thought the game was realistic/relevant and fun, and they learned new information about opioids. Participants reported increased confidence to refuse opioids and decreased likelihood of accepting opioids from someone they know. Knowledge about opioids increased (P < 0.006), and adolescent perception that prescription drugs are safer than illegal drugs decreased (P < 0.003) after playing SafeUse.Conclusion: Findings suggest that SafeUse is acceptable and likely educational to adolescents and worthy of further development and research.