Clinical and pathophysiologic studies were performed in five unrelated children with primary distal renal tubular acidosis who were diagnosed during infancy and followed for 3 to 9 1/2 years. All patients had permanent defects in hydrogen ion secretion, sodium reabsorption, and concentrating capacity. A transient, age-related, proximal tubular defect in sodium and bicarbonate reabsorption was also present. Renal bicarbonate wasting was mainly observed during the first years of life and progressively decreased with advancing age. Glomerular filtration rate remained within normal limits. Following sustained therapy with sodium and potassium bicarbonate, the patients had optimal growth, arrest of progression of nephrocalcinosis, and lack of other characteristic features of the disease with the exception of polyuria. Dosage of alkali was mainly determined by the magnitude of the renal bicarbonate loss and decreased progressively from a maximum of 3.9 to 10.0 mEq/kg/day during the first year of life to about 3 mEq/kg/day at or beyond 6 years of age. The total dosage of alkali required could be derived by the sum of the urinary excretion of bicarbonate plus 2 mEq/kg/day, which represents mean endogenous acid production. Although calciuria was normal when metabolic acidosis was corrected, patients with higher urinary sodium excretion had higher urinary excretion of calcium and thus were at greater risk of developing nephrocalcinosis if therapy was not carefully controlled.