Intravascular malignant lymphomatosis (IML) is a rare disorder of small and medium size vessels that frequently goes undiagnosed until the time of autopsy. The clinical courses of two such patients were examined to determine factors that would facilitate antemortem diagnosis. Both patients had mental status changes, pyramidal tract signs, and peripheral neuropathy. Despite postmortem evidence of widespread lymphocytic invasion of vessels throughout the body including peripheral and central nervous systems, neuroimaging studies, cerebrospinal fluid analysis, peripheral blood studies, and bone marrow biopsy failed to reveal diagnostic evidence of the underlying neoplastic process. Although markedly abnormal, nerve conduction studies were nonspecific. Familiarity with IML and its consideration in the differential diagnosis when central and peripheral nervous system dysfunction occur concurrently may guide the physician to tissue biopsy facilitating antemortem diagnosis and institution of appropriate therapy.