We evaluated the prognostic significance of immunologic inhibitory biomarkers in head and neck squamous cell carcinoma (HNSCC) patients undergoing definitive chemoradiotherapy (CRT). Thirty patients were prospectively enrolled. Plasma levels of soluble MHC class I polypeptide-related sequence A (sMICA) and transforming growth factor-β1 (TGF-β1) were measured before and 2 weeks after CRT. The median follow-up was 32.9 months (range: 12.4-40.6 months). The pre-treatment sMICA (p < 0.001) and TGF-β1 (p < 0.001) levels were significantly increased in HNSCC patients, compared to healthy controls. In HNSCC patients, the median pre-CRT and post-CRT sMICA levels were 43.1 pg/mL and 65.3 pg/mL, respectively, while the median pre-CRT and post-CRT TGF-β1 levels were 57.7 ng/mL and 36.0 ng/mL, respectively. After CRT, 19 patients (63.3%) exhibited persistently elevated sMICA, six patients (20.0%) exhibited persistently elevated TGF-β1, and five patients (16.7%) exhibited persistently elevated sMICA and TGF-β1. Patients with persistently elevated sMICA and TGF-β1 after CRT experienced an earlier tumor progression (p = 0.030), and poor overall survival (p = 0.010). Our results suggest that HNSCC patients who exhibit persistently elevated sMICA and TGF-β1 levels after CRT are at higher risk of tumor progression or death.