BACKGROUND Nosocomial diarrhea affects 12% to 32% of hospitalized patients. Before the development of the Clostridium difficile cytotoxin assay in the 1970s, Staphylococcus aureus was frequently implicated as a cause of hospital-acquired infectious colitis, particularly in association with recent antibiotic therapy or abdominal surgery. Decreased utilization of stool culture has reduced the recognition of S. aureus as a rare, but historically important, cause of enterocolitis. CASE REPORT An 81-year-old man with no recent history of travel, exposure to potential infectious sources (e.g., sick contacts, animals, undercooked foods), or antibiotic or proton-pump inhibitor use was admitted for a Whipple procedure (expanded intraoperatively with total pancreatectomy, splenectomy, and portal vein resection) for stage III pancreatic adenocarcinoma. On postoperative day (POD) 5, the patient developed large-volume watery diarrhea that did not improve with tube feeding cessation and oral pancreatic enzyme replacement. He subsequently became clinically septic on POD10, and workup revealed severe radiographic sigmoid and rectal colitis and methicillin-resistant S. aureus (MRSA) bacteremia. Polymerase chain reaction testing for C. difficile was negative twice (POD5 and POD12). He was diagnosed with MRSA proctocolitis and improved with initiation of oral and intravenous vancomycin. CONCLUSIONS We describe a case of staphylococcal enterocolitis, a previously common cause of nosocomial diarrhea that has become increasingly underappreciated since the advent of culture-independent stool testing for C. difficile. Increased awareness of this entity, especially when Clostridium assays are negative, may guide more effective treatment of hospital-acquired infection.