The purpose of this study was to gain new insights in the role of succinylcholine in the initiation of malignant hyperthermia (MH). The intravenous (IV) administration of succinylcholine (2.0 mg/kg) induced fasciculations and masseter spasm in both normal swine and those susceptible to MH. However, the amplitudes and durations of generalized fasciculations were significantly greater in the susceptible animals that subsequently developed a fulminant episode of MH: succinylcholine induced not only tachycardia, hyperthermia, contractures, and increases in PaCO2 and lactate, all classic indicators of an episode, but also an initial severe hypotension. The mean arterial pressure in these swine decreased from 115 ± 6 mm Hg to 60 ± 12 mm Hg (X̄ ± SD), 1 min after the administration of succinylcholine. Normal swine developed neither cardiovascular effects nor altered metabolism in response to succinylcholine. The pretreatment of animals with a nondepolarizing muscle relaxant (pancuronium 0.1 mg/kg) minimized fasciculations induced by succinylcholine, but did not prevent the hypotension nor episodes of MH in the susceptible swine. In the pretreated and untreated susceptible swine, dantrolene was an equally effective treatment. Plasma catecholamine levels after succinylcholine administration were increased only in the susceptible swine without the pancuronium pretreatment. We concluded that the effects of succinylcholine on skeletal muscle and/or on other tissues play a significant role in the initiation of a MH episode in swine with this genetic disorder, and that these effects are not dependent on an abnormal sensitivity for succinylcholine-induced skeletal muscle fasciculations in these animals.