Experimental myotonia induced in rat muscle by ClC-1 chloride channel-inhibited has been shown to be related inversely to extracellular concentrations of Mg(2+) and Ca(2+) ([Mg(2+) ]o and [Ca(2+) ]o) within physiological ranges. Because this implicates a role for [Mg(2+)]o and [Ca(2+)]o in the variability of symptoms among myotonia congenita patients, we searched for similar effects of [Mg(2+)]o and [Ca(2+)]o on myotonia in human muscle. Bundles of muscle fibers were isolated from abdominal rectus in patients undergoing abdominal surgery. Myotonia was induced by ClC-1 inhibition using 9-anthracene carboxylic acid (9-AC) and was assessed from integrals of force induced by 5-Hz stimulation for 2 seconds. Myotonia disappeared gradually when [Mg(2+)]o or [Ca(2+)]o were elevated throughout their physiological ranges. These effects of [Mg(2+)]o and [Ca(2+)]o were additive and interchangeable. These findings suggest that variations in symptoms in myotonia congenita patients may arise from physiological variations in serum Mg(2+) and Ca(2+).