Background To evaluate the prognostic significance of plasma proinflammatory cytokines in patients with head and neck squamous cell carcinoma undergoing curative chemoradiotherapy. Methods This prospective study was approved by the IRB of our institute (201406075RINC). Head and neck squamous cell carcinoma non-metastatic patients receiving curative chemoradiotherapy were prospectively enrolled. Proinflammatory plasma cytokines concentrations [interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-γ, and tumor necrosis factor-α] were evaluated at two time points (before chemoradiotherapy, and 2 weeks after completion of chemoradiotherapy). Associations of the plasma level of cytokines and clinical outcomes were evaluated. Results Thirty patients were included. The primary sites of cancer were oropharynx (33%), oral cavity (23%), hypopharynx (23%), larynx (10%), and others (10%). Most patients had stage IV disease. The median radiotherapy dose was 70 Gy in 33 fractions. With a median relative short follow-up of 15.9 months, early tumor recurrence was noted in twelve 12 patients (40%), and death was noted in 6 patients (20%). Among the 8 proinflammatory plasma cytokines, IL-8 and IFN-γ were significantly associated with survival outcomes. The mean IL-8 levels before and after treatment were 1.6 and 4.1 pg/mL, respectively. The mean IFN- γ level before and after treatment were 4.7 and 2.8 pg/mL, respectively. In univariate analysis, stage IV (p = 0.047), persistent elevation (level after treatment was greater than or equal to the level before treatment) of plasma IL-8 (p=0.024) or IFN-γ (p=0.006) were significantly associated with early tumor recurrence and poor overall survival. In multivariate analysis, patients with persistent elevation of plasma IL-8 or IFN-γ, independent of stage, had significantly worse RFS (HR3.0, p = 0.038 for persistent elevation of plasma IL-8; HR 8.8, p = 0.026 for IFN-γ). Conclusions: In patients with head and neck squamous cell carcinoma undergoing curative chemoradiotherapy, persistent elevation of plasma IL-8 or interferon-γ after treatment may predict early tumor recurrence and poor overall survival. Legal entity responsible for the study National Taiwan University Hospital Funding National Taiwan University Hospital Disclosure All authors have declared no conflicts of interest.