Background: Acute cholecystitis is a life-threatening disease process in immunocompromised patients. The purpose of this study is to determine the incidence, clinical course, and management of calculous and acalculous acute cholecystitis in immunocompromised patients. Methods: A single center’s database was queried for all patients with a diagnosis of acute cholecystitis from January 1, 2003 to September 30, 2016 with concomitant diagnosis of neutropenia, leukopenia, leukemia, or lymphoma. These cases subsequently underwent chart review. Data on demographics, diagnostic studies, and management were collected and analyzed. Results: There were 4525 patients diagnosed with acute cholecystitis during the study window. One hundred twenty patients were identified to be immunocompromised at time of diagnosis. Seventy-nine patients (65.8%) had acute calculous cholecystitis while 41 patients (34.2%) had acalculous cholecystitis. There were no significant demographic differences between calculous and acalculous groups. There was similar use of percutaneous cholecystostomy tube (7.6%, 9.8%, p = 0.69), laparoscopic cholecystectomy (70.9%, 61.0%, p = 0.27), and open cholecystectomy (10.3%, 2.4%, p = 0.13) in both calculous and acalculous groups. Discussion: While immunosuppression is commonly thought to be associated with acalculous cholecystitis, our data suggest the majority of acute cholecystitis in immunocompromised patients are calculous. Most patients in our studies were managed successfully with laparoscopic cholecystectomy with acceptably low complication rates. Conclusion: Calculous cholecystitis is more common than acalculous cholecystitis in immunocompromised patients. Both are often managed successfully with laparoscopic cholecystectomy with very low rates of conversion to open cholecystectomy.