Vaping is the most prevalent form of tobacco use among youth in the United States. Motivated by the certainty effect in prospect theory, this study investigated the role of uncertainty tolerance as a potential moderator of the effects of gain- vs. loss-framed text messages for youth vaping prevention. Youth susceptible to future vaping (N = 536) were randomized to view a series of eight gain- or loss-framed text messages about the health consequences of vaping. Cognitive and affective responses to the messages as well as beliefs, attitude, and intentions about vaping were assessed post-exposure. Results showed an overall advantage of the loss frame on several outcomes. Additionally, an interaction between framing and uncertainty tolerance was observed for most outcomes such that the loss frame was more effective for those high in uncertainty tolerance, while the gain frame held a slight edge for those low in uncertainty tolerance. Findings from this study have implications for further engaging prospect theory in message framing research. They may also inform audience segmentation and targeted message design for youth vaping prevention efforts.