Background: Multiple perforations in the small bowel as cytomegalovirus (CMV) related immune reconstitution inflammatory syndrome (IRIS) in an human immunodeficiency virus (HIV)-infected patient is very rare. Up to now, only five IRIS-associated cases including our case were reported. We performed pathological examination, metagenomic next-generation sequencing (mNGS), CMV and immune cells immunohistochemical staining for rapid diagnosis and differential diagnosis.Case presentation: We describe a case with multiple perforations in the small bowel as CMV related IRIS in an HIV-infected patient. The patient appeared multiple perforations in the small bowel after 26 days of antiretroviral therapy (ART). The patient underwent exploratory laparotomy. Partial resection and surgical repair of small intestine were performed. CMV enteritis was confirmed by immunohistochemistry staining and other opportunistic infections were excluded by mNGS. However, he died from intestinal obstruction and septic shock at 55 days after surgery. Conclusions: Perforations due to CMV related IRIS are very rare, and usually lack the prodromal period symptoms of abdominal pain and diarrhea. It is not easily foreseen and appears shortly after ART. The condition of intestinal perforations is lethal, and early identification and surgical treatment are lifesaving.