Sporadic colorectal cancer remains a significant driver of worldwide morbidity and mortality. Environmental factors associated with colorectal cancer are increasingly well-described and now include generalized colonic dysbiosis and individual enteric bacteria. Clostridioides difficile is one such species, with recent mouse model work suggesting prolonged exposure to C. difficile toxin B is conducive to colonic tumorigenesis. However, there is a dearth of real-world human evidence linking C. difficile exposure and colorectal cancer. Herein, we analyzed a multicenter, longitudinal, electronic health record-based dataset to test the association between C. difficile test positivity and the risk of incident colorectal cancer utilizing unadjusted and multivariable (controlled for clinical conditions independently associated with colorectal cancer development) Cox proportional hazard modeling to compare C. difficile exposed and nonexposed cohorts. We found that individuals who tested recurrently positive for C. difficile had a significantly increased risk of incident colorectal cancer [adjusted HR (aHR) 2.05 (95% confidence interval, 1.27-3.29)] compared with those who tested positive only once [aHR 0.70 (0.45-1.10)] or never. Furthermore, we found potential trends that the effect of C. difficile test positivity on the risk of incident colorectal cancer was stronger amongst females compared with males. These findings help translate emerging mouse model work on C. difficile-influenced colorectal tumorigenesis and lay groundwork for more substantial human investigations into this connection. These findings also may begin to help guide the personalized deployment of novel fecal microbiota-based therapies designed to interrupt the life cycle of C. difficile within the gut of human hosts and, potentially, prevent long-term health sequelae of chronic C. difficile infection.