A case report describes the case of a 66-year-old man who was diagnosed with cytomegalovirus retinitis (CMVR) with markedly decreased CD4+ T-cell levels (102 cells/μL), suggesting severe immunodeficiency.[1] The patient initially responded to treatment with ganciclovir, but after five months CMVR returned and new pulmonary nodules appeared.[1] Next-generation metagenomic sequencing has identified a rare lung co-infection caused by the bacterium Tropheryma whipplei and the fungus Penicillium digitatum that has not previously been described as a manifestation of this type of lymphoma.[1] Despite antimicrobial therapy, pulmonary lesions persisted, and a PET-CT scan revealed hypermetabolic lung and lymph node lesions.[1] A subsequent lung biopsy confirmed Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV+ DLBCL-NOS).[1] The case demonstrates that severe, unexplained immunodeficiency with recurrent CMVR and rare opportunistic infections should raise the suspicion of an underlying hematologic malignancy, with definitive diagnosis dependent on histopathologic confirmation.[1]