Background: Clostridium difficile, the most common cause of nosocomial diarrhea, can lead to significant morbidity and mortality. 25% of all pediatric nosocomial C. difficile Infections (CDI) occur in children with cancer. Although the epidemiology of CDI in adults is well described, risk factors for CDI in children with malignancy have not been fully studied. Methods: Using the PHIS database, we created a retrospective cohort of patients ≥1 year old with an ICD-9 code for malignancy who were admitted to participating children's hospitals from 2001-09. CDI was defined by an ICD-9 code, a charge for C. difficile toxin assay and antibiotic treatment for CDI. Pharmaceutical data was analyzed for the 7 days prior to each CDI. A Cox proportional hazards model, adjusted by site and clustered by patient, was created to measure the risk of developing CDI for each hospital admission. The model censored on discharge, stem cell transplantation or death. Results: Of 40,638 admissions of 21,248 children among 41 hospitals, 1,048 CDIs occurred. Analysis by drug class showed that exposure to 3rd and 4th generation cephalosporins was associated with increased risk of CDI. Exposure to 1st generation cephalosporins, macrolides, and H2 acid blockers showed a protective effect. Proton pump inhibitors, fluoroquinolones and clindamycin were not significantly associated with CDI. Individual drug analyses were also performed (Table). Conclusions: This study reports the first risk factor analysis for CDI among children with cancer in an administrative database. Similar to adult studies, risk of CDI increased with broad spectrum antibiotics. Unlike prior studies, ciprofloxacin showed a protective effect against CDI in children with cancer. Further study and confirmation of risk factors for CDI in children with malignancy may help guide antibiotic use and CDI screening programs.