Project Abstract The continuing HIV epidemic in the U.S. remains a critical health issue for young priority populations bearing a disproportionate burden of infection. Daily oral PrEP (and as of December 2021, a long-acting injectable cabotegravir) is safe and effective in reducing the risk of sexual HIV acquisition in adults and adolescents, yet PrEP awareness/usage remains low. Accordingly, interventions are sorely needed to address PrEP awareness and mitigate potential barriers related to PrEP use. One such intervention modality is social media (SM), as HIV knowledge, PrEP awareness, and communicating issues, such as access and cost, are easily addressable via clear SM messages on platforms young people already use frequently. Given that PrEP awareness/usage remains low and that SM may be a viable intervention modality for increasing PrEP facilitators and reducing barriers, the overall objective of this proposed exploratory research project is to 1) characterize the SM landscape regarding PrEP and HIV prevention messages and 2) develop new and improved behavioral theory-based messages about PrEP that are clear, specific, consistent, and scientifically up to date. With a robust and multidisciplinary team across 2 institutions, we will accomplish this objective via 3 SPECIFIC AIMS: AIM 1: Characterize PrEP-related communications across 3 popular social media platforms (Facebook, Instagram, and Twitter), identifying message and source characteristics. Using content analytic methods, we will access, human code, and analyze publicly available PrEP-related SM posts/messages, describing features of messages, posters/users, and social networks. AIM 2: Build a predictive, explainable health communication model, guided by the Multilevel Model of Meme Diffusion (M3D), to determine the diffusion potential of PrEP-related messages. We will apply machine learning methods to characterize PrEP message features; develop/evaluate a predictive model of a message diffusion potential using large-scale training data; and apply the model to predict a set of online diffusion metrics for a given message and assess its ability to reach online PrEP-relevant populations. AIM 3: Develop and pilot test PrEP promotion messages, for several young priority populations, for implementation/evaluation in a future project. Using human- centered design (HCD) principles, we will engage 2-3 end-user segments in iterative rounds of SM message development and testing. This proposed R21 will yield a deeper understanding of PrEP promotion messaging on SM and produce a “library of messages,” tailored for several young priority populations at risk for HIV. Such messages will be empirically tested in a future R01 project, and assessed for evidence of behavior change (i.e., PrEP usage). Such knowledge may be employed in innovative/targeted efforts via well-liked and accessible digital tools, such as SM, effectively supporting the updated National HIV/AIDS Strategy for the U.S.