Cholestyramine, a chlorinated anion exchange resin, acts as a bile acid sequestrant by forming an indigestible compound with bile acids. It effectively reduces diarrhea by sequestering the bile acid salts in the duodenum. However, the chloride ions of cholestyramine can exchange for bicarbonates (HCO3-) in the small intestine, which causes the loss of HCO3- and the increase level of free chloride reciprocally in the blood. Two elderly patients diagnosed with the stage 3a~4 of chronic kidney disease (CKD) were on the long-term respirator. These two patients suffered from severe diarrhea and were both treated with cholestyramine. A short course of cholestyramine treatment briefly alleviated patients’ diarrhea condition but rapidly led to a more serious hyperchloremic metabolic acidosis (HCMA). Because both patients had a pre-existing CKD condition in conjunction with pneumonia, urosepsis, oliguric acute kidney failure (ARF), and chronic respiratory alkalosis due to long-term use of ventilator, the compensatory function for the HCO3- resorption in the kidney may be severely perturbed. The dysfunctional kidney function may further aggravate the cholestyramine-induced HCMA in these two patients. Without the renal dialysis, the conditions of these two patients worsened and eventually caused the death of these two patients. In conclusion, the use of cholestyramine for treating severe diarrhea needs to be cautious, especially for the high-risk patients having a pre-existing kidney disease.