Primary hepatosplenic CD5-positive diffuse large B cell lymphoma (CD5⁺ DLBCL) has recently been characterized as showing hepatosplenomegaly without lymphadenopathy, a portal and intrasinusoidal pattern of infiltration in the liver, and bone marrow invasion by lymphoma cells, without intravascular involvement. A 45-year-old man presented with fever and malaise in June 2013. Computed tomography showed hepatosplenomegaly and multiple liver tumors without lymphadenopathy. An ultrasonography-guided needle biopsy of the liver mass revealed portal and intrasinusoidal infiltration of CD5⁺CD20⁺ lymphoma cells and large numbers of destroyed hepatocytes. These findings were diagnostic of primary hepatosplenic CD5⁺ DLBCL. Upon admission, lymphoma cells also appeared in the peripheral blood and serum hepatocyte growth factor (HGF) was markedly elevated. A bone marrow biopsy revealed extensive invasion by lymphoma cells. Seven days after admission, his laboratory data showed elevated aminotransferase and serum creatinine levels. Therefore, dose-reduced CH(O)P, with rituximab (R-CHOP) therapy, plasma exchange, and continuous hemodiafiltration, was initiated. The patient achieved complete remission after 4 courses of R-CHOP therapy. HGF is useful for predicting acute liver damage. If the HGF level is high, remission induction therapy, with plasma exchange, is necessary at an early stage.