ObjectiveThe shortage of organs donated for transplantation is a global concern. Even though increasing awareness can boost organ donation registration rates (thus leading to a higher number of available organ transplants), public organ donation campaigns lack effectiveness and are rarely tailored to audiences. To further enhance the effectiveness of digital health (i.e., organ donation) communication, we assessed the perception of social media organ donation campaign strategies (i.e., transformational, informational, neutral) as a function of personality traits (i.e., Big Five). MethodData was collected through an online experiment with 1000 participants (i.e., German citizens between 18 and 70 years) who were recruited via Facebook and Prolific between Jun–Aug 2022. Perceived message effectiveness of the organ donation posts was measured on a 5-point Likert scale applying the AIDA model and consequently analyzed using multiple regression analyses. ResultsMessaging strategy applied in the social media campaigns served as a predictor for message effectiveness depending on the personality traits of the audience when controlling for demographics and donor status. Extraversion was positively associated with higher message effectiveness of the transformational post while neuroticism showed a significant positive association with informational content. Agreeableness was positively correlated with transformational as well as informational post effectiveness. Furthermore, higher perceived post effectiveness increased the likelihood to sign-up for further organ donation information. ConclusionOur results show that Instagram in Germany is an underleveraged but potentially effective platform to spread organ donation knowledge. Based on our results, we urge public health authorities to revisit and start tailoring their (digital) health (i.e., organ donation) campaigns to audiences (i.e., personality traits) to increase their effectiveness.