Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. HUS can be secondary to multiple etiologies such as infections, medications, and immune processes. A rare, yet significant, etiology of HUS includes acute Clostridium difficile colitis. Here, we present a case of atypical HUS secondary to acute C. difficile colitis, successfully treated with hemodialysis and systemic corticosteroids. It is imperative that clinicians are cognizant of C. difficile-associated HUS given the overall rising incidence of acute C. difficile infections.