Although individual attacks of hypokalemic periodic paralysis are lessened by potassium treatment, recurrence is frequently not prevented by prophylactic potassium administration. Twelve patients with hypokalemic periodic paralysis were treated with acetazolamide in a placebo-controlled trial. Whereas the majority had failed to improve with previous therapy, 10 of the 12 patients were dramatically improved by acetazolamide. This response has been maintained for periods of 16 to 43 months with minimal or no side effects. Several patients previously disabled are now asymptomatic. In addition to eliminating attacks of weakness, acetazolamide also improved interattack weakness in 8 of 10 affected patients. The mechanism of effect of acetazolamide was not discovered. Acetazolamide produced a mild metabolic acidosis but did not have a demonstrable effect on total body sodium, total body potassium, or thyroid function. Acetazolamide is the most effective treatment available for hypokalemic periodic paralysis.