The multidisciplinary assessment of functioning in patients with head and neck cancer (HNC) according to the "ICF Core Set for Head and Neck Cancer" (ICF-HNC) was developed in an international and multi-disciplinary approach. The ICF-HNC is an application of the ICF that was adopted by the World Health Organization. The objective of this study was to test whether categories of the ICF-HNC can discriminate among clinically relevant differences in patients. This was a cross-sectional multicentre study in which 267 patients with HNC from 11 different countries participated. All categories were tested within a cumulative logit model to identify which ICF-categories show differences in tumour location, staging, treatment modalities and time since treatment. In the comprehensive ICF-HNC, 84 of the tested categories (76%) reflect differences in at least one of the given parameters. In the Brief ICF Core Sets for HNC (ICF-HNC), all 19 categories (100%) reflect differences. Two categories (social relationships and economic self-sufficiency) showed significant differences among all tested criteria. Most categories of the ICF-HNC are sensitive to clinically relevant differences in the study population. Especially, the ICF component "activities and participation" holds categories with high discriminative ability for clinically relevant differences. These aspects should be carefully included into rehabilitation plans for HNC.