Introduction Intrahepatic cholestasis is a rare but potentially fatal complication of sickle cell anemia (SCA). It is due to widespread sickling within the hepatic sinusoids leading to ischemia. Hypoxic damage leads to ballooning of hepatocytes and intrahepatic cholestasis. Case Report A 23-year-old male with a history of SCA presented to an outside facility with right upper quadrant pain and jaundice. Laboratory investigations revealed a total bilirubin of 27.6 mg/dL, ALT 54 IU/L, AST 96 IU/L, ALP 72 IU/L, INR 1.2, WBC 16×109/L, and hemoglobin 6.9 g/dL. CT scan of the abdomen showed intra- and extrahepatic biliary dilation with choledocholithiasis. The gallbladder was distended with stones. IV hydration, packed red blood cells, and antibiotics were given for possible cholangitis. ERCP revealed multiple stones within the CBD which could not be extracted because of their size. Therefore, ERCP was repeated with successful lithotripsy. A CBD stent was inserted and complete stone removal was accomplished with sphincterotomy and balloon extraction. Laparoscopic cholecystectomy was then performed. However, total bilirubin continued to rise, up to 42 mg/dL (direct fraction 34.4 mg/dL). Despite that, it was decided to discharge the patient home with close outpatient follow-up, given the resolution of his pain. However, four days later, he presented to our hospital with worsening abdominal pain, fatigue and icterus. He was hemodynamically stable and afebrile. Laboratory investigations revealed a WBC count of 23×109/L, hemoglobin 8.2 g/dL, total bilirubin of >70.2 mg/dL (direct was >10 mg/dL), ALT 79 IU/L, AST 86 IU/L, ALP 156 IU/L, INR 1.2, LDH 950 IU/L and reticulocyte count was 19.0%. Viral hepatitis serology was negative. MRCP revealed mild dilation of the CBD and intrahepatic biliary tree without residual stones. Moreover, there were scattered foci of peripheral wedge-shaped enhancement without washout, which were consistent with transient hepatic intensity differences. Given the overall picture, sickle cell intrahepatic cholestasis (SCIC) was diagnosed. Exchange transfusion (ET) was performed with rapid clinical improvement and gradual drop of bilirubin (Figure 1).Figure: Total bilirubin trend (in mg/dL) for the patient. He was discharged from the outside facility despite rising bilirubin. Upon presentation to our hospital, his bilirubin was above maximum level of detection for our laboratory, which is 70.2 mg/dL.Conclusion We present a case of SCA complicated by obstructive jaundice due to choledocholithiasis. Rising bilirubin despite successful stone extraction promoted attention toward possible SCIC. Early recognition and aggressive ET in severe cases are crucial for positive outcomes.