The effect of water deprivation on lithium clearance was studied in rats with lithium-induced polyuria. During a 3-hr period of water deprivation, the rats lost water in amounts corresponding to about 10% of body weight. Lithium clearance fell to about 25% of the level observed in rats which were not water deprived. During shorter periods of water deprivation, the fall of lithium clearance was less. The decrease of lithium clearance was partly due to a fall of inulin clearance and partly due to a fall of fractional excretion of lithium. The decrease of the two variables contributed to the same extent to the decrease of lithium clearance. The findings support the suggestion that insufficient intake of water in patients with lithium-induced polyuria may lead to a rapid lowering of lithium clearance and, hence, to a rise of the serum lithium concentration and development of intoxication.