Our aim in this article is to propose a new hypothesis concerning the etiology of renal tubular acidosis (RTA) in that subgroup of patients who have the isolated, primary type of proximal RTA. We suggest that their underlying disorder is a more alkaline intracellular pH of the proximal convoluted tubule. Increased alkalinity of proximal tubular cells would explain the low rate of bicarbonate reabsorption per liter glomerular filtration and the decreased rate of ammonium excretion despite a low urine pH and the presence of chronic metabolic acidosis. Additional diagnostic tests to evaluate this hypothesis in this specific subgroup of patients with proximal RTA are also outlined.