An 80-year-old man was diagnosed with diffuse large B-cell lymphoma (DLBCL) and rectal cancer at the same time. After six cycles of DLBCL treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHO-nisR), lymphoma lesions regressed. Subsequently, neoadjuvant chemoradiotherapy of rectal cancer with tegafur–uracil/leucovorin (UFT/UZEL) was started. On the 18th day, a fever of 38.3 °C appeared, on the 24th day, neutropenia and thrombocytopenia of the 4th degree. Treatment with G-CSF, antibiotics and recombinant human soluble thrombomodulin (rTM) was started for disseminated intravascular coagulopathy (DIC), but the response was poor and acute respiratory distress syndrome (ARDS) developed on day 34. Bone marrow biopsy confirmed hemophagocytosis by macrophages, hemophagocytic syndrome (HPS) caused by Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections was diagnosed. Despite antiviral treatment, the patient died on day 37. The article emphasizes the importance of early diagnosis of HPS in case of fever of unknown origin and decrease in blood cells during treatment of malignant disease.