Abdominal pain in an immunocompromised patient represents a common clinical scenario that may have uncommon causes. Evaluation relies first on identifying the immunocompromise, whether due to congenital immunodeficiencies, malignancy, hematopoietic stem cell transplant, solid organ transplant, or human immunodeficiency virus/acquired immunodeficiency syndrome. Based on this determination, the emergency physician may then build a focused differential of pathophysiologic possibilities. Careful evaluation is necessary given the absence of classic physical examination findings, and liberal use of laboratory and cross-sectional imaging is prudent. Conservative evaluation and disposition of these high-risk patients is important to consider.