Cytomegalovirus (CMV) colitis occurs commonly in immunocompromised patients with high mortality. CMV infection has also been reported in immunocompetent individuals and it has a varied clinical presentation. When HIV-infected patients are started on antiretroviral therapy (ART) there is a reconstitution of the immune system which results in the paradoxical worsening of existing conditions or development of new disease conditions known as immune reconstitution inflammatory syndrome (IRIS). In the setting of IRIS one of the most common infections to occur is non-tubercular mycobacteria (NTM). The infection generally develops when the CD4 count is < 50 cells/µL. Here we present a rare case of CMV colitis followed by NTM infection in the setting of IRIS, its management, and treatment outcomes.