STUDY DESIGN: Retrospective database analysis. OBJECTIVE: To investigate incidence, comorbidities, and impact on health care resources of Clostridium difficile infection after lumbar spine surgery. SUMMARY OF BACKGROUND DATA: C. difficile colitis is reportedly increasing in hospitalized patients and can have a negative impact on patient outcomes. No data exist on estimates of C. difficile infection rates and its consequences on patient outcomes and health care resources among patients undergoing lumbar spine surgery. METHODS: The Nationwide Inpatient Sample was examined from 2002 to 2011. Patients were included for study based on International Classification of Diseases, Ninth Revision, Clinical Modification, procedural codes for lumbar spine surgery for degenerative diagnoses. Baseline patient characteristics were determined and multivariable analyses assessed factors associated with increased incidence of C. difficile and risk of mortality. RESULTS: The incidence of C. difficile infection in patients undergoing lumbar spine surgery is 0.11%. At baseline, patients infected with C. difficile were significantly older (65.4 yr vs. 58.9 yr, P<0.0001) and more likely to have diabetes with chronic complications, neurological complications, congestive heart failure, pulmonary disorders, coagulopathy, and renal failure. Lumbar fusion (P=0.0001) and lumbar fusion revision (P=0.0003) were associated with increased odds of postoperative infection. Small hospital size was associated with decreased odds (odds ratio [OR], 0.5; P<0.001), whereas urban hospitals were associated with increased odds (OR, 2.14; P<0.14) of acquiring infection. Uninsured (OR, 1.62; P<0.0001) and patients with Medicaid (OR, 1.33; P<0.0001) were associated with higher odds of acquiring postoperative infection. C. difficile increased hospital length of stay by 8 days (P<0.0001), hospital charges by 2-fold (P<0.0001), and inpatient mortality to 4% from 0.11% (P<0.0001). CONCLUSION: C. difficile infection after lumbar spine surgery carries a 36.4-fold increase in mortality and costs approximately $10,658,646 per year to manage. These data suggest that great care should be taken to avoid C. difficile colitis in patients undergoing lumbar spine surgery because it is associated with longer hospital stays, greater overall costs, and increased inpatient mortality. LEVEL OF EVIDENCE: 3.