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Background Clostridioides difficile (C. difficile) is the major pathogen causing antibiotic-associated diarrhea. There are a variety of symptoms associated with C. difficile infection (CDI) in adults, including self-limiting diarrhea, pseudomembranous colitis, toxic megacolon, septic shock, and even death from the infection. However, the infant's intestine appears to be completely resistant to the effects of C. difficile toxins A and B with rare development of clinical symptoms. Case presentation In this study, we reported a 1-month-old girl with CDI who was born with neonatal hypoglycemia and necrotizing enterocolitis. Her symptom of diarrhea occurred after extensive use of broad-spectrum antibiotics during hospitalization and was accompanied by elevated white blood cell, platelet, and C-reactive protein levels, and repeated routine stool examinations were abnormal. She was recovered by norvancomycin (an analogue of vancomycin) and probiotic treatment. The results of 16 S rRNA gene sequencing also demonstrated the recovery of intestinal microbiota with the enrichment of Firmicutes and Lactobacillus. Conclusions Based on the literature review and this case report, clinicians should also pay attention to diarrhea caused by C. difficile in infants and young children. More strong evidence is needed to explain the true prevalence of CDI in this population and to better understand the C. difficile-associated diarrhea in infants. Keywords: Clostridioides difficile, CDI, Antibiotic-associated diarrhea, Intestinal microbiota, Infant, Author(s): Zhirong Li[sup.1], Ning Dong[sup.1], Jihong Hao[sup.2], Zirou Ouyang[sup.1], Cuixin Qiang[sup.1], Ying Yang[sup.1], Chaoyi Mi[sup.3], Yanan Niu[sup.1], Jing Yang[sup.1], Baojiang Wen[sup.1], Liwei Wang[sup.5], Shaodan Zhang[sup.4,6] and Jianhong Zhao[sup.1,2,6] Introduction Clostridioides [...]