Clostridioides difficile infection (CDI or C-diff), also known as Clostridium difficile infection, is a symptomatic infection due to the spore-forming bacterium Clostridioides difficile. Symptoms include watery diarrhea, fever, nausea, and abdominal pain. It makes up about 20% of cases of antibiotic-associated diarrhea. Antibiotics can contribute to detrimental changes in gut microbiota; specifically, they decrease short-chain fatty acid absorption which results in osmotic, or watery, diarrhea. Complications may include pseudomembranous colitis, toxic megacolon, perforation of the colon, and sepsis.

Clostridioides difficile infection is spread by bacterial spores found within feces. Surfaces may become contaminated with the spores with further spread occurring via the hands of healthcare workers. Risk factors for infection include antibiotic or proton pump inhibitor use, hospitalization, other health problems, and older age. Diagnosis is by stool culture or testing for the bacteria's DNA or toxins. If a person tests positive but has no symptoms, the condition is known as C. difficile colonization rather than an infection.

Prevention efforts include terminal room cleaning in hospitals, limiting antibiotic use, and handwashing campaigns in hospitals. Alcohol based hand sanitizer does not appear effective. Discontinuation of antibiotics may result in resolution of symptoms within three days in about 20% of those infected. The antibiotics metronidazole, vancomycin or fidaxomicin, will cure the infection. Retesting after treatment, as long as the symptoms have resolved, is not recommended, as a person may often remain colonized. Recurrences have been reported in up to 25% of people. Some tentative evidence indicates fecal microbiota transplantation and probiotics may decrease the risk of recurrence.

C. difficile infections occur in all areas of the world. About 453,000 cases occurred in the United States in 2011, resulting in 29,000 deaths. Global rates of disease increased between 2001 and 2016. C. difficile infections occur more often in women than men. The bacterium was discovered in 1935 and found to be disease-causing in 1978. In the United States, healthcare-associated infections increase the cost of care by US$1.5 billion each year. Although C. difficile is a common healthcare-associated infection, at most 30% of infections are transmitted within hospitals. The majority of infections are acquired outside of hospitals, where medications and a recent history of diarrheal illnesses (e.g. laxative abuse or food poisoning due to Salmonellosis) are thought to drive the risk of colonization.