This paper presents an observational study of the longitudinal effects of cancer treatment on quality of life (QoL) in patients treated for head and neck squamous cell carcinoma (HNSCC), and evaluated the contribution of patients' baseline illness cognitions to the prediction of QoL 2 years after diagnosis. One hundred seventy-seven patients eligible for primary treatment for HNSCC completed the Illness Perception Questionnaire-Revised at baseline and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire-30 at baseline, at 1-year and 2-year follow-ups. Compared to baseline, patients reported better emotional functioning at both follow-ups (p < 0.001), worse social functioning at 12 months (p < 0.05), and better global health status at 24 months (p < 0.05). Patients' own implicit common sense beliefs about their illness added small but significant amounts of variance to the prediction of QoL after 2 years. Less belief in own behavior causing the illness predicted better functioning and better global health. Strong illness identity beliefs predicted worse functioning and worse global health. Negative perceptions about the duration of the illness (chronic timeline beliefs) and more negative perceived consequences also predicted worse QoL. Our results on the negative perceptions about the duration of the illness, perceived consequences, and high symptom awareness predicting worse QoL illustrate the detrimental effects of uncertainty and negative expectations about the future course of the illness. The identification of these cognitive factors provides possible targets for counseling strategies to assist patients in long-term adjustment to HNSCC.