BackgroundAlthough organ transplantation is a very effective clinical solution to save the lives of patients suffering from organ failure, the supply of donated organs still cannot meet its growing demand. Educating the society about organ donation is a critical success factor in increasing donation rates, especially in countries that require potential donors to proactively register and opt-in (e.g., Germany). While social media has emerged as an effective tool for disseminating health information, recent evidence suggests that published organ donation content (both online and offline), aimed at raising awareness, still lacks effectiveness. To develop recommendations for optimizing organ donation messaging via social media, this study not only examines the current state of organ donation communication on Instagram, but also identifies factors that contribute to message effectiveness.MethodsWe conducted a retrospective content analysis to in-depth assess organ donation-related content published on Instagram in Germany between January and March 2022. Systematic coding allowed to identify common themes, sentiments, and communication strategies, which were analyzed for their effectiveness using linear regression analyses.ResultsOf the 500 organ donation posts, 57% were published by institutional authors while the remainder was shared by private accounts. Most content was aimed at the general population and shared neutral (80%) or positive sentiments (17%). Transformative messages, positive emotions, posts published by the transplant recipient and the image of a human served as predictors for post effectiveness measured in terms of likes (p< 0.001) and comments (p< 0.01). Sharing personal experiences (p< 0.01) and highlighting the meaning of organ donations (p< 0.05) resulted in significantly higher audience engagement than any other topic discussed.ConclusionOur findings highlight the need for health officials to work closely with organ transplant recipients to publicly advocate for organ donations by sharing personal and transformative messages. The high share of posts published by transplant recipients indicates a certain openness to share personal experiences with broad audiences. Different message characteristics served as predictors for message effectiveness (i.e., increased audience engagement) which can likely be extrapolated to other health-related use cases (e.g., cancer screening).Supplementary InformationThe online version contains supplementary material available at 10.1186/s12889-023-15736-2.