Clostridium difficile infection (CDI) is the primary cause of community- and health care-associated diarrhea. CXCL10, also known as IFN-γ-inducible protein of 10 (IP-10), is involved in various inflammatory diseases, but its role in CDI remains unknown. In this study, We determined the serum concentration of CXCL10 in 80 CDI patients and 76 sex & age-matched diarrhea patients by enzyme-linked immunosorbent assay (ELISA) and analyzed the correlation between CXCL10 levels and CDI disease severity parameters. Besides, we also measured the level of other cytokines and/or chemokines in CDI patients, such as IL-1β, IL-6, TNF-α and CXCL9. We found that serum CXCL10 in CDI patients was significantly higher compared with those in non-C. difficile diarrhea patients, especially in the moderate disease. Elevated serum CXCL10 correlated positively and significantly with severity score index (SSI) score in all CDI patients. CXCL10 levels were also positively correlated with WBC count, creatinine and inflammatory cytokines including, IL-1β, IL-6 and CXCL9, but negatively correlated with albumin. Furthermore, serum CXCL10 concentration could be significantly decreased after effective treatment of CDI. Therefore, the above results suggest that the up-regulated release of CXCL10 is important in the immunopathogenesis of CDI, and may be served as a potential alternative biomarker for the monitoring of CDI disease severity and therapeutic efficacy.