Cytomegalovirus (CMV) pulmonary involvement is rarely associated with IRIS; therefore, limited information is available. Here, we describe the case of a 43-year-old HIV-infected male who developed an unusual case of IRIS after cytomegalovirus (CMV) pneumonia. Clinically there was a progressive and paradoxical worsening of respiratory distress, despite being treated for CMV after initiation with antiretroviral therapy. Chest X-ray revealed disseminated infiltrates in both lungs; chest CT-scan showed generalized lung involvement and mediastinal adenopathy. Pulmonary biopsy confirmed CMV pneumonia with the observation of typical viral inclusions on pneumocytes. CMV pneumonia can be associated with the development of IRIS requiring treatment with immunosuppressant's and immunomodulatory drugs.