C. difficile is a Gram-positive, anaerobic bacterium that forms resistant spores that enhance its transmission. It was discovered in 1935 and named Bacillus difficile because of the problems in culturing it. Three years later was re-named Clostridium difficile and in 2017 became Clostridioides difficile. In 1974, an article entitled Clindamycin-Associated Colitis described the watery diarrhea and pseudomembranes that characterize a C. difficile infection [1]. Currently, it is the most common cause of hospital-acquired diarrhea [2]. While C. difficile colitis has always been an important problem to diagnose and treat effectively, the years of COVID-19, with the widespread and increased use of antibiotics and the debility associated with the virus, have amplified the danger posed by this bacterium. This chapter discusses the factors contributing to risk of developing C.difficile infection.