Lyme disease is a multisystem disorder resulting from infection by the tick-borne spirochete, Borrelia burgdorferi. Fever, chills, malaise and headaches; a characteristic rash; and subsequent polyarthritis typically herald the onset of this condition. Neurologic involvement may occur with skin and joint manifestations or present alone as meningitis, cranial neuritis, and radiculopathy known as Bannwarth's syndrome. We report the cerebrospinal fluid (CSF) cytomorphologic and immunocytochemical features of four patients who presented with isolated meningitis, cranial neuritis, and painful neuropathy without initial history of specific skin rash or previous tick bite. Initial CSF findings of significant numbers of markedly atypical plasmacytoid mononuclear cells suggested CSF non-Hodgkin's malignant lymphoma. Immunocytochemical studies on CSF specimens, however, revealed polyclonal surface immunoglobulin patterns consistent with an inflammatory reaction. Follow-up clinical history and/or peripheral blood serologic testing for antibody titers with B. burgdorferi antigen confirmed the diagnosis of Lyme disease in all four cases. We conclude that Lyme disease may present as atypical spinal fluid lymphoplasmacytic cellular infiltrates that simulate malignant lymphoma and that appropriate immunocytochemical studies and peripheral blood serologic testing be performed to establish this diagnosis and direct appropriate therapy.