Introduction: Diffuse large B-cell lymphoma (DLCL) commonly presents in the seventh decade of life and spreads aggressively to extra-nodal tissues. DLCL, when responding to therapy, has a long-term survival rate of 50%. The complications of DLCL are multifold. A literature review has revealed only one report of sclerosing cholangitis (SC) as a complication of B-cell lymphoma. In contrast, a recent meta-analysis has described an association between hepatitis C virus (HCV) infection and DLCL. We present a patient with chronic HCV infection, who was diagnosed with DLCL and secondary SC. Case Report: A 45-year-old Caucasian female with a six-year history of HCV infection, genotype 1b, presented with vague acute abdominal pain. Physical examination revealed jaundice, pruritus and choluria. The patient experienced mild dyspnea, but denied fevers or sweats. Laboratory analysis showed a total bilirubin (TB) of 4.5 mg/dL, with direct predominance, alkaline phosphatase (AP) of 272 mg/dL and AST of 59 mg/dL. An abdominal CT scan showed scattered, hypodense hepatic foci, suggestive of a diffuse, infiltrative process. There was extensive abdominal lymphadenopathy and mild ascites. A CT-guided liver biopsy showed DLCL. Due to progressive cholestasis (TB = 22.5 mg/dL and AP = 330 mg/dL) an ERCP was performed, showing several areas of narrowing interspersed with dilations in the intra-hepatic bile ducts, consistent with diffuse SC. No dominant stricture was seen; therefore, endoscopic intervention was not performed. Following chemotherapy, the patient achieved an excellent response with resolution of clinical, radiographic and laboratory abnormalities. Discussion and Conclusion: Secondary SC refers to a radiological and clinical syndrome that is similar to primary SC but results from a known pathogenesis or injury, including obstructive, toxic, ischemic, and neoplastic causes. In this report, we describe a patient with chronic HCV infection who developed DLCL complicated by secondary SC. In conclusion, secondary SC should be suspected with unexplained cholestasis complicating DLCL.