Normal resting potential (P1) of myofibers follows the Nernst equation for K⁺ with about -85 mV at normal [K⁺]_o=4 mM. Hyperpolarization occurs with decreased [K⁺]_o, although at [K⁺]_o<1.0 mM myofibers paradoxically depolarize to another stable potential of -60 mV (P2). Gramicidin-induced leaks increased the relative frequency of P2 rat myofibers from 25% to 50% at [K⁺]_o=2.5 mM. In contrast, [K⁺]_o needed to be reduced to 1.5 mM to shift half of control fibers to P2. Increasing frequency of P2 fibers decreased twitch force of myofiber bundles. Acetazolamide diminished the frequency of P2 fibers and increased force. The findings mimic hypokalemic periodic paralysis (HypoPP), a muscle channelopathy characterized by weakness at reduced serum [K⁺]. In myofibers taken from seven HypoPP patients, up to 25% of the myofibers were in P2 at [K⁺]_o=4 mM, in accordance with their permanent weakness, and up to 99% were in P2 at [K⁺]_o=1.5 mM, in accordance with their paralytic attacks. Of 36 HypoPP patients, 25 had permanent weakness and myoplasmic [Na⁺]_i overload, up to 24 mM, as shown by in-vivo ²³Na-MRI. Acetazolamide normalized [Na⁺]_i and increased muscle strength. HypoPP myofibers showed a nonselective cation leak of 12–19.5 mS/cm² which may explain the Na⁺ overload. The leak makes myofibers more sensitive to reduced serum [K⁺] and the resulting membrane depolarization causes the weakness. We postulate that the principle of paradoxical depolarization upon [K⁺]_o reduction that underlies HypoPP pathogenesis may apply to other tissues, such as heart or brain, when they become leaky, for example, due to ischemia.