The influence on urinary acidification of prolonged ingestion of a high potassium diet was explored in normal men and dogs. In men, the response to acute ingestion of ammonium chloride was assessed in a paired fashion after 5 days of ingesting a formula diet of normal or high potassium content; whereas in animals chronically ingesting a small amount of hydrochloric acid, the response to an increase in daily potassium intake was assessed. Urine pH was lower in the potassium-loaded state with both these models, and the effect persisted in the dog studies as long as a high potassium intake was continued. The decrease in urine pH could not be accounted for by changes in plasma acid-base status, net acid excretion, rate of urine flow, urine ionic strength, or fixed buffer excretion, i.e., phosphate, creatinine, or organic acids. Studies of men with administration of exogenous aldosterone and studies of adrenalectomized dogs with constant, maintenance steroid replacement indicated that the decrease in urine pH does not result from altered aldosterone secretion.In the human studies the largest decreases in urine pH were associated with a concomitant diminution in both ammonium and net acid excretion, suggesting a primary decrease of ammonia diffusion into the urine. These events during potassium loading, which are the mirror image of changes during potassium depletion, suggest that the relation between potassium, urine acidification, and ammonia metabolism may play an important role in the maintenance of hydrogen ion and possibly potassium homeostasis during alterations in potassium intake.