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Simple Summary: Cancer-related fatigue (CRF) is a common side-effect of cancer and its treatments, but few studies have investigated CRF in head and neck cancer. Using data from 2847 patients included in the Head and Neck 5000 prospective clinical cohort, we investigated CRF over 12 months from cancer diagnosis. At baseline, shortly after diagnosis, 27.8% of patients had CRF. This rose to 44.7% at 4 months and fell to 29.6% at 12 months. In adjusted models, the likelihood of having CRF over 12 months was significantly higher in patients who were female, current smokers, and had comorbid conditions or depression at baseline. It was also higher in patients with stage 3 or 4 disease and who had multimodal treatment. The high prevalence of CRF indicates that there is a need for additional interventions and supports for affected HNC patients; these could be targeted towards patients in the higher risk groups. Cancer-related fatigue (CRF) is a common side-effect of cancer and its treatments. For head and neck cancer (HNC), CRF may exacerbate the symptom burden and poor quality-of-life. Using data from the Head and Neck 5000 prospective clinical cohort, we investigated clinically important CRF over a year post-diagnosis, assessing temporal trends, CRF by HNC site and treatment received, and subgroups at higher risk of CRF. Recruitment was undertaken in 2011–2014. Socio-demographic and clinical data, and patient-reported CRF (EORTC QLQ-C30 fatigue subscale score ≥39 of a possible 100) were collected at baseline (pre-treatment) and 4- and 12- months post-baseline. Mixed-effects logistic multivariable regression was used to investigate time trends, compare cancer sites and treatment groups, and identify associations between clinical, socio-demographic and lifestyle variables and CRF. At baseline, 27.8% of 2847 patients scored in the range for clinically important CRF. This was 44.7% at 4 months and 29.6% at 12 months. In the multivariable model, after adjusting for time-point, the odds of having CRF over 12 months were significantly increased in females and current smokers; those with stage 3/4 disease, comorbidities and multimodal treatment; and those who had depression at baseline. The high prevalence of clinically important CRF indicates the need for additional interventions and supports for affected HNC patients. These findings also identified patient subgroups towards whom such interventions could be targeted. [ABSTRACT FROM AUTHOR]