CD3ζ has emerged as a clinically important immunological marker in head and neck squamous cell carcinoma (HNSCC) with reduced level of expression reported in both tumor infiltrating lymphocytes and peripheral blood lymphocytes. In this prospective study (power = 0.99, α  = 0.05), CD3ζ expression was compared in 47 HNSCC patients and 53 controls using standardized flow cytometric method. There was no statistical difference in the percentages of the CD3 ε+ T‐cell subset present in the peripheral blood mononuclear cells of the HNSCC patients and the healthy controls; however, T cells from the HNSCC patients produced a significantly weaker IFN‐γ response in comparison to the healthy controls, when they were stimulated by the recall viral CEF peptide antigen. All patients were followed up for at least 3 years with a median follow‐up of 45 months. Levels of CD3ζ‐chain expression were measured at 117 follow‐up visits at six‐month intervals. Receiver operating characteristic curve identified the optimal cut off as a 12% increase in post treatment CD3ζ‐chain expression from the baseline levels to confirm absence of HNSCC with the area under curve of 0.81 (95% CI = 0.68–0.94) for predicting absence of HNSCC. The specificity, sensitivity and positive predictive value were 81.25% 79.21% and 97.56%, respectively. Three‐year disease specific survival (DSS) was significantly lower ( p  = 0.007) at 63.2% for patients who showed <12% increase in CD3ζ‐chain level as compared to 96.2% for patients who had ≥12% increase. Our results indicate that the change in CD3ζ‐chain expression from the baseline is an independent predictor of residual and recurrent HNSCC. What's new? There is an urgent need for biomarkers that allow early detection of relapse in head and neck squamous cell carcinoma (HNSCC). CD3ζ may be one such marker, as lymphocytes from HNSCC patients express reduced levels of this protein. In this study, the authors found that patients whose CD3ζ levels increased by less than 12% after treatment had significantly lower survival. These results indicate that measurement of CD3ζ over time may allow oncologists to detect and treat recurrence early enough to improve outcomes.