A 60-year-old male was referred to our hospital because of cervical lymphadenopathy and a left hilar abnormal shadow seen on chest X-ray in May 1999. The pathological findings of the cervical lymph nodes revealed that the patient had a malignant lymphoma, of the diffuse large B cell type, at clinical stage IIIB. Immunohistochemistry demonstrated that the lymphoma cells were positive for CD11a, CD19, CD20, CD23, CD25, CD45, IgM, IgD and lambda, but negative for CD5. Although a complete remission was obtained after 8 courses of CHOP therapy, the patient relapsed 32 months later. Two courses of a half dose of CHASE therapy consisting of CPM, ara-C, VP-16 and dexamethasone, followed by rituximab (600 mg/week x4) resulted in a transient re-induction of complete remission. However, multiple cutaneous tumors became apparent just 10 days after the last rituximab therapy. Immunohistochemistry of the cutaneous tumors revealed infiltration of CD20-negative lymphoma cells. A series of chemotherapy including high-dose MTX was ineffective, and the patient died in August 2003. Autopsy findings revealed the systemic intra-capillary infiltration of CD20 negative-lymphoma cells into multiple organs, including the lungs, liver, and kidneys. A CD20 negative-clone selected by rituximab therapy appeared to have expanded in this case.