Malignant hyperthermia (MH) can be triggered in swine either by stress or by certain anesthetic agents. In humans, MH commonly occurs in patients previously exposed uneventfully to triggering anesthetics. This variability in expressivity of the MH syndrome is a combination of unknown genetic and environmental factors. A hypothesis was tested that a fall in rectal temperature following general anesthesia can prevent the MH syndrome in susceptible patients. Nine littermate Pietrain pigs with MH were exposed to halothane after their rectal temperatures were stabilized at 35°, 36°, and 37° C during thiopental/nitrous oxide anesthesia. Thein vivoMH metabolic, cardiopulmonary, and contracture responses were attenuated at the lower rectal temperatures. The effect of varying temperatures on biopsies of skeletal muscle from these animals showed a marked decrease in contracture response to halothane when the muscle was cooled to 25° C. Studies on the Ca2+uptake process and on Ca2+channel-Ca2+release properties of isolated sarcoplasmic reticulum (SR) membranes showed that increasing incubation temperatures from 25° to 38° C increased the Ca2+uptake rate by the SR Ca2+pump and also increased the probability of Ca2+-induced Ca2+opening of a Ca2+channel and the release of stored Ca2+. This study indicates that temperature can have a marked effect on the expressivity of the MH defect at the whole animal, isolated tissue, and fragmented membrane levels of organization. Since many surgical patients' temperatures decrease after induction and anesthesia, this may explain one environmental factor that determines the incidence, rate, and magnitude of the MH syndrome.