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The risk of Clostridium difficile infection (CDI) has not been well studied in patients with lymphoma. We thus sought to determine the risk of CDI in hospitalizations with lymphoma along with its trend, outcomes, and predictors using a large database.Hospital discharge data from the Nationwide Inpatient Sample (NIS) from 2007 to 2011 were used for the study. Using the International Classification of Diseases, Ninth Revision, Clinical Modification codes, all adult patients aged 18 years or older having a primary diagnosis of lymphoma were queried for the presence of CDI as any of the secondary diagnoses. The risk of CDI in lymphoma and its yearly trend were assessed. We performed multivariate logistic regression to determine the independent risk factors of CDI in lymphoma. Furthermore, we studied mortality and other adverse outcomes of CDI in patients with lymphoma.There were 236,312 discharges (weighted) with the primary diagnosis of lymphoma. CDI was present in 2.13% of patients with lymphoma versus 0.8% in the nonlymphoma group (P < 0.001). On multivariate analysis, the significant predictors of CDI in lymphoma were presence of infection (odds ratio [OR] 3.1, 95% confidence interval [CI] 2.7–3.6), stem cell transplant (OR 2.7, 95% CI 2.3–3.4), graft-versus-host disease (OR 1.9, 95% CI 1.4–2.8), race (Asian vs white, OR 1.6, 95% CI 1.1–2.4), chemotherapy (OR 1.6, 95% CI 1.4–1.8), gastrointestinal surgery (OR 1.4, 95% CI 1.2–1.7), and Charlson Comorbidity Index (CCI) (CCI of 2 vs 0–1: OR 1.2, 95% CI 1.1–1.4; CCI of 3 vs 0–1: OR 1.3, 95% CI 1.03–1.6). CDI in lymphoma was associated with worse hospital outcomes such as increased mortality (17% vs 8%), increased length of stay (23.6 vs 9.9 days), mean total hospital charges ($197,015 vs $79,392), rate of intubation (13% vs 4% vs 13%), and rate of total parenteral nutrition (11% vs 3%).Hospitalization with lymphoma was associated with an increased risk of CDI. The significant predictors for CDI in lymphoma were infection, stem cell transplant, graft-versus-host disease, race, chemotherapy, gastrointestinal surgery, and Charlson Comorbidity Index. CDI in lymphoma was associated with increased mortality and other adverse outcomes warranting a need of more vigilance for CDI in patients with lymphoma.