The mechanism of the decrease in plasma potassium induced by phosphate treatment was investigated in a 24-year-old hypertensive patient with hypophosphatemic osteomalacia, who was the youngest of four patients, belonging to a 23 number kindred of five generations. Parameters of potassium, sodium, calcium, and phosphate metabolism as well as specific renal functions have been studied in the basal state and during administration of graded doses of phosphate (500-6000 mg). Progressive hypokalemia developed during phosphate treatment. An inverse correlation was found between plasma potassium and doses of phosphate (plasma potassium = -0.2 g phosphate + 3.9 r = -0.49; p < 0.05; N = 21). A renal route of potassium loss was suspected, but could not be confirmed as potassium excretion did not increase although sodium excretion was augmented [basal sodium output: 56.7 mmol/24 h; phosphate treatment: 153 mmol/24 h (p < 0.05)]. Transtubular potassium gradient (TTKG) also decreased and an inverse correlation was found between TTKG and doses of phosphate (r = -0.37; p < 0.02; N = 38). Decrease of TTKG was possibly the result of suppressed K+ secretion. It was concluded that potassium loss occurred by a non-renal (intestinal) route in phosphate-induced hypokalemia. Although major hazards of treatment of hypophosphatemic osteomalacia with phosphate and calcitriol are secondary hyperparathyroidism and vitamin D intoxication, potassium loss also should be kept in mind.