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We explored the mediation effect of cognitive factors on the relationship between cancer-related online information seeking and cancer-preventative behaviors. Using data obtained from the National Cancer Institute’s 2013 Health Information National Trends Survey (N = 2,896), we performed structural equation modeling and demonstrated that online information seeking about cancer did not decrease users’ cancer fatalism; however it elevated users’ level of self-efficacy. Moreover, the findings show that cancer-related information seeking indirectly influenced cancer-preventative behaviors via self-efficacy, and individuals’ level of self-efficacy significantly mediated the association between fatalistic beliefs and cancer-preventative behaviors. The results call for attention to cognitive mediators in explaining the relationship between online information seeking and related behaviors.