(-) Emetine (0.25-2.0 mg/kg i.p.) was administered to rats for up to 220 days. At doses of 1.0 mg/kg or less, the animals continued to gain weight but more slowly than the untreated control animals. The physiologic changes in the muscles from these animals were minimal; there was a small reduction in both the resting membrane potential and in the maximum rate of rise of the action potential. There was no atrophy or loss of muscle fibres although in the occasional muscle, hyaline fibres, necrotic fibres and split fibres were observed. There was a focal loss of myofibrillar adenosine triphosphatase (ATPase) and nicotinamide adenine dinucleotide tetrazolium reductase (NADH TR) in Type II and Type III fibres, but no such loss in Type I fibres. The animals receiving 2.0 mg/kg of (-) emetine gained weight slowly for up to 20 days but then rapidly lost weight and by 30 days they were weak and emaciated. The muscles from these animals were severely atrophied and the total muscle wet weight was reduced by almost 20%. The strength of the muscles from these animals was measured in vitro using direct stimulation. They were weaker than normal both in absolute terms and when expressed in terms of tension developed/unit wet weight. There was no evidence of either functional or structural denervation but surgically denervated muscles from animals in this group were indistinguishable from denervated muscles from normal rats. Severe structural damage was obvious in the fibres of both extensor digitorum longus and soleus. Necrotic, hyaline and splitting fibres were common and the focal loss of myofibrillar ATPase and NADH TR activity was extensive and occurred in Type I fibres as well as in Type II and Type III fibres. It is concluded that the muscular weakness induced by (-) emetine is due to a direct effect on the muscle fibres and that this occurs at a subcellular level. There is no evidence that functional or structural denervation plays any role in the etiology of emetine myopathy in the rat.