The chronic renal and systemic acid-base effects of hyperparathyroidism in humans remain controversial and unresolved. The present studies evaluated the acid-base response of normal human subjects to a 13-day intravenous infusion of synthetic b(1-34) PTH sufficient to result in sustained hypercalcemia and hypophosphatemia. The acid-base response was biphasic: an initial transient renal acidosis developed on the first day of PTH infusion, followed by a prompt increase in net acid excretion and plasma [HCO3-] of sufficient magnitude to result in a steady state of mild metabolic alkalosis. The results indicate that: 1) sustained, continuous, experimentally produced hyperparathyroidism results in a steady state of mild metabolic alkalosis; 2) the alkalosis is both generated and maintained, at least in part, by renal mechanisms; and 3) reported renal acidosis in sustained clinical conditions of primary hyperparathyroidism is not attributable to either direct or indirect effects of PTH excess when present for a 2-week period, an interval sufficient to re-establish a new steady state of renal and systemic acid-base equilibrium.