In order to assess the pathogenesis of myopathological alterations induced by zidovudine, we studied muscle samples from 21 patients infected by human immunodeficiency virus with zidovudine myopathy. Cytochrome c oxidase histoenzymatic reaction was evaluated in skeletal muscle fibres and arterial smooth muscle cells. Other investigations included immunocytochemistry for membrane attack complex and endomysial capillary counts. All patients had partial cytochrome c oxidase deficiency. A perifascicular distribution of cytochrome c oxidase-deficient fibres was found in 14 of 21 patients. Cytochrome c oxidase-deficient fibres were significantly more frequent in perifascicular areas than in the complete muscle sections (28% vs 12%, P < 0.001). Cytochrome c oxidase-deficient arteries were found in 11 patients, of whom 10 also had a perifascicular deficiency. Mononuclear microvascular inflammation was observed in four patients and membrane attack complex deposition in capillary walls in two patients. The capillary counts were not significantly different in the patients and in the controls. These results suggest that, in addition to a direct action of zidovudine on mitochondrial DNA, chronic muscle ischaemia related to zidovudine-induced vascular dysfunction might be implicated at the inception of muscle damage in zidovudine myopathy.