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Background Antibiotic exposure is common among children with leukemia. However, limited data exist regarding the risk of Clostridium difficile infection (CDI) across anti-pseudomonal β-lactam antibiotics commonly used for fever and neutropenia. Methods A multicenter cohort of children with newly diagnosed acute lymphoblastic leukemia (ALL) was established from 43 freestanding children's hospitals from 1999 to 2009. Patients were followed until their index CDI event, defined by the CDI ICD-9 code plus a C difficile test charge, or until 180 days from ALL diagnosis. Cox proportional hazards models were performed to identify the hazards of CDI after exposure to anti-pseudomonal β-lactams, adjusting for demographics, other antibiotic exposures, severity of illness, antacids, gastrointestinal manipulation, and confounding by hospital. Results A cohort of 8268 ALL patients was assembled; median age was 5.5 years (interquartile range, 3.26–10.58). Two-hundred sixty-eight (3.2%) patients developed CDI within 180 days of ALL diagnosis. Each 1-day increase in exposure to an anti-pseudomonal β-lactam within the prior 30 days was associated with a significantly increased risk for CDI (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.01, 1.09). Ceftazidime (HR, 1.05; 95% CI, 1.02, 1.08) and cefepime (HR, 1.07; 95% CI, 1.02, 1.12) were each independently associated with CDI. Conclusions Efforts to reduce total exposure to anti-pseudomonal β-lactam agents may help to reduce the risk of CDI in children with newly diagnosed ALL. Cefepime and ceftazidime were independently associated with CDI, whereas anti-pseudomonal penicillins and carbapenems were not. These findings, if confirmed, have potential implications for antibiotic choice during periods of fever and neutropenia. [ABSTRACT FROM PUBLISHER]