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In the context of health communication, humor often functions as a “vehicle for the message” (Cernerud & Olsson, 2004, p. 397). However, studies illustrate both positive and negative humor effects. The impact of humor in health messages thus seems to be contingent on intervening factors (Lee et al., 2015). Whereas most studies have focused on humor in explicit health messages, little is known about the persuasive impact of humor in fictional narratives. Specifically, a test of differences between humorous and serious depictions of health issues in narratives is lacking. In two models, we assumed the impact of humorous versus serious narrative presentations of three health issues on empathy to be mediated by perceived humor, narrative engagement and counterarguing. An online experiment with a 3 (topic: diabetes, depression, drug abuse) x 2 (presentation: humorous vs. serious) between-subjects design with 248 participants was conducted. Serial mediation analyses confirmed both proposed models.