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Background: Results from previous studies on a possible interaction between smoking and Epstein–Barr virus (EBV) in the risk of multiple sclerosis (MS) are conflicting. Objectives: To examine the interaction between smoking and infectious mononucleosis (IM) in the risk of MS. Methods: Within the case–control study on Environmental Factors In Multiple Sclerosis (EnvIMS), 1904 MS patients and 3694 population-based frequency-matched healthy controls from Norway, Italy, and Sweden reported on prior exposure to smoking and history of IM. We examined the interaction between the two exposures on the additive and multiplicative scale. Results: Smoking and IM were each found to be associated with an increased MS risk in all three countries, and there was a negative multiplicative interaction between the two exposures in each country separately as well as in the pooled analysis (p = 0.001). Among those who reported IM, there was no increased risk associated with smoking (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.66–1.37). The direction of the estimated interactions on the additive scale was consistent with a negative interaction in all three countries (relative excess risk due to interaction (RERI): −0.98, 95% CI: −2.05–0.15, p = 0.09). Conclusion: Our findings indicate competing antagonism, where the two exposures compete to affect the outcome. [ABSTRACT FROM AUTHOR]