The aims of this study were to evaluate the validity and reliability of self-reported measurements of comorbidity, as well as the impact of comorbidity on health-related quality of life (HRQoL) scores, obtained at the time of diagnosis and at 18 months follow-up, among head and neck squamous cell carcinoma (HNSCC) patients treated with curative intent. One hundred and six (106) patients were available for analyses at the time of diagnosis and 72 patients at 18 months follow-up. HRQoL was assessed with the EORTC QLQ-C30/H&N35 inventories. The presence of comorbidities was assessed with a self-reported eight-question-based questionnaire at the time of diagnosis and after 18 months, as well as retrospectively with the Adult Comorbidity Evaluation (ACE-27) scale. The self-reported eight-question-based assessments of comorbidity showed high reliability with the chart-based ACE-27 inventory at both time points (r = 0.611, p < 0.001 and r = 0.612, p < 0.001). Significant correlations with comorbidity were determined for the functional (r = -0.194, r = -0.269) and the general symptom HRQoL sum score (r = 0.257 and r = 0.334) at the time of diagnosis and after 18 months; in particular present lung disease explained these associations. The covariates marital status, smoking status, alcohol consumption, and tumor stage were also found to be significantly associated with HRQoL sum scores at both time points. In conclusion, we have demonstrated that it is possible to assess comorbidity in HNSCC patients by self-reported questionnaires. Moreover, comorbidities, in particular present lung disease, appear to have an important and unique influence on HRQoL scores.