Swallowing function in patients with head and neck cancer (HNC) is often assessed pre-treatment, during and at intervals post-treatment to identify those with dysphagia as early as possible. This study aims to investigate the minimal clinical important difference (MCID) for the 100 mL water swallow test (100 mL WST) to increase its utility in clinical practice and in clinical trials. Data from 211 HNC patients, treated byeither single or combined modality were included. Patients completed both the 100 mL WST and M.D. Anderson Dysphagia Inventory (MDADI) at baseline (i.e., prior to treatment) and 12 months post-treatment. The MCID for the 100 mL WST was calculated using two approaches of the anchor-based method (using the MDADI), including mean change, and ROC curve. Additionally, the distribution-based method was used utilizing the half standard deviation approach. In the anchor-based method, a 4 mL/s in the 100 mL WST was defined as an MCID for deterioration, with a sensitivity of 75% and a 1-specificity of 46%. In contrast, a change of 5 mL/s was deemed as an MCID for improvement, based on the distribution-based method. The findings showed that deterioration of 4 mL, or an increase of 5 mL from baseline to 12 months post-HNC treatment equates to an MCID from the patients' perspective. Based on these findings, it may be beneficial to increase the utilization of the 100 mL WST in clinical practice to observe the changes, and in clinical trials to interpret and compare different study arms.