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Abstract Background The urokinase-type plasminogen activator receptor (uPAR) plays an essential function in leukocytes and endothelial homeostasis and, therefore, in the development of chronic periodontitis. Methods The study enrolled 150 participants, 50 chronic periodontitis with head and neck cancer post radiotherapy (CP + HNC post-RT) patients, 50 chronic periodontitis (CP) without HNC patients, and 50 healthy controls. Clinical Attachment Loss (CAL), Probing Pocket Depth (PPD), Plaque Index (PI), and Gingival Bleeding Index (GBI) were recorded. An enzyme-linked immunosorbent assay (ELISA) was constructed to quantify serum (suPAR) levels. Results Stage and grade of periodontitis were stage III-IV, grade C in patients (CP + HNC post-RT), stage I-III, grade A/B in patients (CP without HNC), and absent in (healthy). Chronic periodontitis with HNC post-RT patients presented a significantly higher proportion of suPAR levels (506.7 pg/ml) compared to chronic periodontitis without HNC and healthy controls (423.08 pg/ml and 255.9 pg/ml), respectively. A significant positive correlation was found between serum suPAR levels and CAL, PPD, PI, and GBI in the periodontal disease groups. ROC results of suPAR (AUC = 0.976 for CP + HNC post-RT, AUC = 0.872 for CP without HNC). Hyposalivation appeared in patients (CP + HNC post-RT; 0.15 [0.11–0.23] ml/min, P = 0.001) and (CP without HNC; 0.30 [0.25–0.41] ml/min, P = 0.001), compared to healthy controls; 0.35 [0.28–0.54] ml/min, P = 0.001). Conclusion The study showed a significant elevation in serum suPAR levels in CP + HNC post-RT patients compared to the CP without HNC and control groups. Clinical trial registration The study was registered retrospectively; clinicaltrials.gov identifier: NCT06529588. Date of registration: July 31, 2024 https://clinicaltrials.gov/study/NCT06529588 .