Normal resting potential (P1) of myofibers follows the Nernst equation, exhibiting about −85 mV at a normal extracellular K⁺ concentration ([K⁺]_o) of 4 mM. Hyperpolarization occurs with decreased [K⁺]_o, although at [K⁺]_o < 1.0 mM, myofibers paradoxically depolarize to a second stable potential of −60 mV (P2). In rat myofiber bundles, P2 also was found at more physiological [K⁺]_o and was associated with inexcitability. To increase the relative frequency of P2 to 50%, [K⁺]_o needed to be lowered to 1.5 mM. In the presence of the ionophore gramicidin, [K⁺]_o reduction to only 2.5 mM yielded the same effect. Acetazolamide normalized this increased frequency of P2 fibers. The findings mimic hypokalemic periodic paralysis (HypoPP), a channelopathy characterized by hypokalemia-induced weakness. Of myofibers from 7 HypoPP patients, up to 25% were in P2 at a [K⁺]_o of 4 mM, in accordance with their permanent weakness, and up to 99% were in P2 at a [K⁺]_o of 1.5 mM, in accordance with their paralytic attacks. Of 36 HypoPP patients, 25 had permanent weakness and myoplasmic intracellular Na⁺ ([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 μS/cm², which may explain the Na⁺ overload. The leak sensitizes myofibers to reduced serum K⁺, and the resulting membrane depolarization causes the weakness. We postulate that the principle of paradoxical depolarization and loss of function upon [K⁺]_o reduction may apply to other tissues, such as heart or brain, when they become leaky (e.g., because of ischemia).