ABSTRACTBackground and AimsLeucine Zipper 4 (LUZP4)‐immunoglobulin G (IgG) is a novel antibody implicated in germ cell tumor‐related paraneoplastic neurologic syndrome. We report a case of painful, progressive tetraparesis associated with testicular seminoma and LUZP4‐IgG seropositivity.Case ReportA 51‐year‐old male presented with a 5‐week history of lower limb predominant progressive weakness. Nerve conduction studies (NCS) and electromyography (EMG) revealed a subacute axonal polyradiculoneuropathy. MRI lumbar spine showed thickening of the cauda equina and enhancement of the lower thoracic spinal cord/conus. Cerebrospinal fluid (CSF) showed a lymphocytic pleocytosis, three oligoclonal bands, and mildly elevated protein. Initial treatment with intravenous immunoglobulin (IVIG) and prednisone produced temporary improvement. CT targeted retroperitoneal lymph node biopsy revealed a seminoma, which was treated with orchiectomy and chemotherapy. The testicular tissue was consistent with a regressed germ cell tumor. His course was subsequently refractory to IVIG, prednisone, and plasma exchange. LUZP4 antibodies were detected in serum, prompting treatment with cyclophosphamide and prednisone. At the 4‐month follow‐up, the patient had significant improvement in hand strength and had transitioned from walker to cane.InterpretationLUZP4‐IgG seropositivity and identification of retroperitoneal seminoma confirmed a paraneoplastic neurologic syndrome, which is a CD8+ T‐cell‐mediated disorder. Aggressive immunotherapy was initiated, resulting in clinical improvement. This case underscores the importance of identifying specific serologic biomarkers that can inform therapeutic decisions and improve outcomes.