Summary: Fluorescence-activated cell sorting and reverse transcription-polymerase chain reaction were used to examine cerebrospinal fluid and blood before and during treatment of a patient with diffuse large B cell lymphoma. A monoclonal population of IgM-expressing B cells that used a rearranged VH4 heavy chain variable region and Vκ3 light chain variable region was found. The persistent monoclonal B cell response in cerebrospinal fluid correlated with neurologic deterioration during treatment.