Rimmed vacuole formation, tubulofilamentous nuclear inclusions and muscle fiber atrophy are the characteristic pathological findings in distal myopathy with rimmed vacuoles (DMRV). Necrotic muscle fibers were few in number and did not appear to account for the muscle weakness, but the nuclear changes with myofibrillar degeneration followed by rimmed vacuole formation appeared to be the major reason for the muscle fiber atrophy in DMRV. To determine whether the nuclear change in DMRV was related to apoptosis, we examined 15 muscle biopsy specimens immunohistochemically, and 7 of them ultrastructurally. The characteristic tubulofilamentous nuclear inclusions were found in 4 and the typical fragmented apoptotic nuclei in 3 of the 7 muscle biopsy samples examined by electron microscopy. TUNEL-positive nuclei reflecting apoptotic DNA fragmentation were found in 13 of 15 biopsies ranging from a few to approximately 1.5% of myonuclei. Apoptosis-specific protein was expressed in the sarcoplasm of atrophic fibers in 13 biopsies both with or without rimmed vacuoles. These findings suggest that the apoptotic process plays a crucial role in myofibrillar degeneration followed by autophagocytosis, i.e., rimmed vacuole formation, in DMRV.