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Dysembryoplastic neuroepithelial tumor (DNET) is a benign central nervous system neoplasm, usually diagnosed in pediatric patients with epilepsy. We describe a case of a 57-year-old man presenting with a first episode of generalized tonic-clonic seizure and subacute cognitive decline, in whom a multicystic right temporal lobe lesion was detected. Further workup led to a new diagnosis of human immunodeficiency virus (HIV) infection. Comprehensive investigations excluded infectious and malignant etiologies. Review of prior imaging, combined with multidisciplinary input, led to a diagnosis of DNET. Two-year follow-up confirmed radiological stability, and the patient remained seizure-free under antiepileptic treatment. This case highlights the importance of expanding the differential diagnosis of cerebral lesions in HIV-positive adults and utilizing prior imaging to guide clinical decision-making.