Objective <p>This investigation evaluates Endothelial Cell-Specific Molecule-1 (Endocan), an endothelial-derived protein, for its capacity to discriminate between healthy and pathological peri-implant tissues and its diagnostic potential in peri-implant disease.</p> Materials and methods <p>This cross-sectional investigation analyzed 62 peri-implant sites from 62 individuals, including 31 healthy sites, chosen according to clinical and radiographic parameters based on 2017 consensus recommendations. Collection of peri-implant crevicular fluid (PICF) utilized paper point methodology, with Endocan quantification performed through enzyme-linked immunosorbent assay (ELISA) techniques. Statistical analysis included multivariable linear regression models to evaluate associations between disease status and Endocan levels, adjusting for demographic factors.</p> Results <p>Endocan levels demonstrated a clear disease progression pattern. Healthy sites showed the lowest levels (643.66 ± 128.49 ng/L), while peri-implantitis sites exhibited significantly elevated concentrations (841.83 ± 62.72 ng/L, <i>p</i> &lt; 0.001). Peri-implant mucositis sites (671.99 ± 133.00 ng/L) were not significantly different from healthy sites (<i>p</i> = 0.757). Modeling demonstrated that peri-implantitis exhibited significant correlation with increased Endocan concentrations (B = 187.74, <i>p</i> &lt; 0.001), while peri-implant mucositis showed no significant association (<i>p</i> = 0.431). Additionally, younger age, female sex, and smoking were independently associated with higher Endocan concentrations.</p> Conclusions <p>Endocan demonstrates specificity as a biomarker for peri-implantitis, showing capacity to differentiate advanced peri-implant pathology from healthy tissues and peri-implant mucositis. These results suggest Endocan’s potential utility for disease staging and monitoring in peri-implant care, providing a foundation for biomarker-based diagnostic approaches in implant dentistry.</p>