Cholestyramine is a nonabsorbable anion exchange resin that is used predominantly for the treatment of hypercholesterolemia in adults and the management of acute diarrhea in children. The authors report two cases of severe hyperchloremic nonanion gap metabolic acidosis associated with the use of cholestyramine therapy. The authors recommend that patients taking cholestyramine who have concomitant renal insufficiency or who are volume depleted or who are taking spironolactone be monitored carefully for the emergence of a hyperchloremic metabolic acidosis.