Susceptibility to malignant hyperthermia is diagnosed by contracture test, which requires an open muscle biopsy sample. We postulated that intramuscular injection of caffeine increases local carbon dioxide pressure (pCO(2)) in individuals susceptible to malignant hyperthermia but not in those who are non-susceptible or in healthy individuals. We measured pCO(2) in the rectus femoris muscle during local stimulation with 500 microL caffeine 80 mmol/L in 12 patients susceptible to malignant hyperthermia, eight non-susceptible individuals, and seven healthy controls. In susceptible individuals, pCO(2) temporarily increased to a maximum of 63 mm Hg (IQR 61-69) compared with 44 mm Hg (43-47) in non-susceptible participants (p=0.003) and 42 mm Hg (41-46) in controls (p=0.003). There were no systemic side-effects. Metabolic monitoring of the highly diffusible CO(2) stimulated by caffeine might allow a minimally invasive test for susceptibility to malignant hyperthermia.