Objectiveto determine if the tumor marker squamous cell carcinoma antigen (SCC‐Ag) observed over time may contribute to the early detection of recurrence, metastasis, and second primary tumors in the follow‐up of patients with head and neck squamous cell carcinoma (HNSCC).Study DesignA retrospective analysis of patients with HNSCC and at least one SCC‐Ag measurement was conducted. Hazard ratios (HRs) were used to determine the correlation between SCC‐Ag and an event.Settingpatients with HNSCC, treated in the Antoni van Leeuwenhoek Hospital in The Netherlands between 2010 and 2020 were used for the analysis.MethodsData from 789 patients were used on event‐free survival (EFS) with time‐dependent Cox models. In addition to current (most recent) SCC‐Ag (also dichotomized into high and low as done for clinical practice), average SCC‐Ag and change between SCC‐Ag measurements (delta SCC‐Ag) were considered, using restricted cubic splines to explore nonlinear relationships.ResultsDichotomized SCC‐Ag values (HR = 3.01, 95% confidence interval [CI]: 2.17‐4.18) and the delta SCC‐Ag (HR = 1.15, 95% CI: 1.07‐1.22) predicted EFS better than models using the cumulative average or current value of SCC‐Ag, also after adjusting for tumor site, stage, age, and gender. A strong association was observed when using delta SCC‐Ag as a linear predictor in the subgroup of oropharynx patients (HR = 4.88, 95% CI: 2.71‐8.79).ConclusionDichotomized and delta SCC‐Ag values can be important markers for EFS, during the follow‐up of patients treated for HNSCC. These results were more evident in patients with oropharyngeal cancer.