A literature search was performed through May 2017. Studies that compared the risk of developing Clostridium difficile infection (CDI) and/or the clinical outcomes of CDI in patients who received statin treatment versus those who did not receive statins were included. Ten observational studies with 37,109 patients were included. Compared to no treatment, statins reduced the risk of CDI development (odds ratio [OR] = 0.66, 95% confidence interval [CI], 0.44–0.99). However, among patients who developed CDI, the use of statins did not significantly reduce recurrent CDI risk (OR = 0.69, 95% CI, 0.28–1.71) or 30-day mortality (OR = 0.77, 95% CI, 0.51–1.14). In conclusion, our study demonstrates a significant association between statin use and a reduced risk of CDI development. However, the findings of our study suggest no significant associations between statin use and improvement in clinical outcomes of CDI. These findings might impact the clinical management and primary prevention of CDI.