A 66 year old man was diagnosed with CNS diffuse large B-cell lymphoma, and underwent treatment with Temozolomide, Dexamethasone, Rituximab, and radiation therapy, and prolonged steroid taper with Dexamethasone. Approximately one month after this, he presented with severe acute hypoxemic respiratory failure, and was admitted to the Medical Intensive Care Unit. Imaging showed diffuse ground glass opacities. Patient underwent diagnostic bronchoalveolar lavage which was positive for Pneumocystis jiroveci. He did not respond well to appropriate therapy and was transitioned to comfort care per his family's wishes, and expired. Pneumocystis jiroveci should always be included in the differential diagnosis of pneumonia in patients treated with Temozolomide, especially when this agent is used in combination with long term, high dose corticosteroids and radiation therapy.