Background: Lipoid Proteinosis (LP), also termed Urbach-Wiethe disease, is an enigmatic genodermato-sis marked by the systemic deposition of hyaline material. With its etiology rooted in ECM1 mutations, LP’s neuropathological spectrum has been hypothesized to involve an array of neurodegenerative biomarkers, underscoring a potential for substantial neurobiological implications. This study endeav-ored to elucidate the serum concentrations of neurodegenerative biomarkers—phosphorylated Tau (pMAPT), S100B, Neuron-Specific Enolase (NSE), Neurofilament Light Chain (NEFL), and Glial Fibrillary Acidic Protein (GFAP)—in LP patients, seeking to establish their diagnostic utility for the condition. Materials and Methods: Fifteen LP patients and 15 matched healthy controls were enrolled. Serum levels of the biomarkers were quantified using ELISA, and their predictive power was assessed through binary logistic regression and Receiver Operating Characteristic (ROC) analysis. Results: Elevated serum levels of NSE, NEFL, and GFAP were observed in LP subjects relative to healthy counterparts, reaching statistical significance (p<0.05). In contrast, pMAPT and S100B levels did not differ appreciably. GFAP is considered a predictive marker for LP with an area under the curve (AUC) value of 0.813 and a 95% confidence interval (CI) of 0.658-0.968 (p=0.003). Conclusions: The study underscores a distinctive neurodegenerative profile in LP, with NSE, NEFL, and GFAP concentrations significantly amplified. These biomarkers, particularly GFAP, may represent novel indicators for LP, offering prospective biomarker-based diagnostic strategies. The insights garnered herein pave the way for advanced understanding and clinical management of LP, delineating a novel avenue for future high-impact research.