The adenosine triphosphate (ATP)–sensitive K⁺ (K_ATP) channel is the most abundant K⁺ channel active in the skeletal muscle fibers of humans and animals. In the present work, we demonstrate the involvement of the muscular K_ATP channel in a skeletal muscle disorder known as hypokalemic periodic paralysis (HOPP), which is caused by mutations of the dihydropyridine receptor of the Ca²⁺ channel. Muscle biopsies excised from three patients with HOPP carrying the R528H mutation of the dihydropyridine receptor showed a reduced sarcolemma K_ATP current that was not stimulated by magnesium adenosine diphosphate (MgADP; 50–100 μM) and was partially restored by cromakalim. In contrast, large K_ATP currents stimulated by MgADP were recorded in the healthy subjects. At channel level, an abnormal K_ATP channel showing several subconductance states was detected in the patients with HOPP. None of these were surveyed in the healthy subjects. Transitions of the K_ATP channel between subconductance states were also observed after in vitro incubation of the rat muscle with low-K⁺ solution. The lack of the sarcolemma K_ATP current observed in these patients explains the symptoms of the disease, i.e., hypokalemia, depolarization of the fibers, and possibly the paralysis following insulin administration.