Severe ulcerous cytomegalovirus pancolitis developed during primary human immunodeficiency virus (HIV) infection in a patient who underwent early combination antiretroviral treatment. This massive inflammatory process led to acute colon perforation. Serological testing demonstrated cytomegalovirus reactivation. Severe immunosuppression caused by primary HIV infection resulted in cytomegalovirus colitis, and initiation of early combination antiretroviral therapy triggered an immune reconstitution inflammatory syndrome potentially leading to colonic perforation.