The monoclonal antibody Py was initially developed as a tool for the identification of subpopulations of hippocampal neurons. Recently it has also been demonstrated to be a useful marker for other populations of midbrain and spinal cord neurons in which the antigen showed a strong colocalization with cytoskeletal elements. To assess the possible usefulness of Py as a tool for studying lesion-induced cell body changes, densitometric analysis of altered Py-immunoreactivity (Py-IR) has been compared with that of microtubule-associated protein 2 (MAP2) in Clarke's nucleus following axotomy. One week after a unilateral transection of the dorsal spinocerebellar tract at Th9-10, Py-IR in the Clarke's nucleus ipsilateral and caudal to the lesion was reduced by approximately 40%. By 21 days, Py-IR was reduced by approximately 50% (a near maximal reduction) and remained constant up to 5 months after the lesion (the longest survival time studied). Alterations of MAP2-IR in Clarke's nucleus were later in onset, slower to develop, and less marked. The differential distribution of the Py antigen in the CNS and its rapid and long lasting loss indicate that the Py antibody is a sensitive tool for studying novel early alterations of the cytoskeleton which may be important molecular events in axotomy-induced pathological processes.