We studied Na transport in red blood cells (RBC) from six patients with hypoparathyroidism (HYPO; 3 postsurgical and 3 idiopathic) and 13 normal subjects. In HYPO, the effect of treatment-induced increases in serum Ca2+ on RBC Na transport also was examined. Na efflux mediated by the ouabain-sensitive Na, K pump and furosemide-sensitive Na, K cotransport (CoT) was examined by flux methodology in RBCs Na loaded to 5 levels of intracellular Na (Na;; 5-90 mM/liter cells) by the p-chloro-mercuribenzene method. The pump-mediated Na efflux was similar in untreated HYPO patients and normal subjects. Correction of hyocalcemia by vitamin D and oral calcium produced a mean increase in serum Ca2+ from 6.62 ± 0.23 (±SEM) to 8.73 ± 0.32 mg/dl. In HYPO patients treated with vitamin D and oral calcium, an increasing serum Ca2+ level was associated with significant (P < 0.01) reductions in pump activity. Further, there was an inverse correlation (r = 0.813; P < 0.001) between serum Ca2+ and pump-mediated Na efflux rate. RBC Na efflux through theCoT pathway was markedly reduced (P < 0.05-0.01) in HYPO patients compared to normal subjects at all levels of Nai. Treatment-induced increases in serum Ca2+ had no effecton the reduced RBC CoT function in HYPO. Thus, changes in ambient serum Ca2+ can modulate the activity of the RBC Na, K pump in HYPO, with increases in Ca2+ inhibiting pump function. The markedly decreased RBC CoT activity was not related to associated hypertension or altered renal function and may represent a primary phenomenon in HYPO. These alterations in RBC Na transport may account for the higher Nai in RBCs of HYPO patients.