Background: The host of costly individual and societal consequences of alcohol, tobacco, and other drugs (ATOD) use underscores the importance of ATOD prevention education. "It's Up 2U" is an evidence-informed, game-based, e-learning ATOD prevention program developed by Children's Health Education Center (CHEC) targeting middle school students. Purpose: That "It's Up 2U" provides the benefits of an engaging e-learning simulation is of little value if it is not effective in appropriately changing ATOD-related attitudes and behavior. This study investigates the overall efficacy of "It's Up 2U," with a focus on students evidencing a number of protective and risk characteristics. Methods: A pre-experimental, pretest-posttest within-subjects design. Discussion: Findings support the overall efficacy of "It's Up 2U." Specifically, participation in "It's Up 2U" was associated with a decrease in reported ATOD use and misperceptions about ATOD use. "It's Up 2U" shows particular promise for decreasing student misperceptions regardless of risk, exposure or protective characteristics. Though a similar association could not be established between ATOD use and risk, exposure or protection factors, additional study with a larger sample is warranted. Translation to Health Education Practice: The relationship of these findings to bystander intervention in bullying education and implications for health education practice are discussed.