<p>Psoriasis is a chronic, immune-mediated skin disease characterized by keratinocyte stress and cytokine-driven inflammation. Glycoprotein 96 (gp-96), a heat shock protein 90 paralog located in the endoplasmic reticulum, plays a critical role in the folding of Toll-like receptors and may contribute to the amplification of inflammatory responses. This study investigated serum gp-96 levels in patients with psoriasis compared to healthy controls and explored potential associations with clinical features. A total of 44 psoriasis patients and 44 healthy individuals were enrolled in a prospective case-control study. Serum gp-96 concentrations were quantified using ELISA. Patients’ demographic and clinical data, including PASI scores, nail and joint involvement, and treatment modalities, were collected. Serum gp-96 levels were significantly higher in psoriasis patients than in healthy controls (median 15.92 vs. 9.33 ng/mL, <i>p</i> &lt; 0.001). However, gp-96 levels did not correlate significantly with PASI score, age, disease duration, or other clinical variables. ROC analysis revealed that serum gp-96 has good diagnostic performance in distinguishing psoriasis patients from controls, with an AUC of 0.83 and an optimal cut-off value of 11.57 ng/mL (sensitivity and specificity: 77.3%). A borderline association with nail involvement was observed, suggesting a potential link between gp-96 levels and localized keratinocyte stress. These findings suggest that gp-96 may be a promising diagnostic biomarker in psoriasis, independent of disease severity, and could play a role in the pathogenesis of the disease through its involvement in ER stress and innate immune activation. Further studies with larger cohorts and tissue-level investigations are warranted to validate these results and explore the therapeutic potential of targeting gp-96 in psoriatic disease.</p>