Patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy (RT) or chemoradiation (CRT) may become immunocompromised. In this population-based study, we aimed to investigate the risk factors, microbiological aetiologies, prognosis and impact on early non-cancer mortality of bloodstream infections (BSIs) after RT/CRT. Patients with HNSCC of the pharynx, larynx and oral cavity treated with curative-intent RT/CRT in Denmark between 2010 and 2017 and subsequent BSI episodes occurring within 18 months of RT/CRT initiation were identified in national registries. We included 5674 patients and observed 238 BSIs. Increasing age, stage and performance status were significantly associated with an elevated BSI risk, while sex, smoking and high-grade mucositis were not. Human papillomavirus-positive oropharyngeal cancer patients had a decreased risk. Staphylococcus aureus accounted for 34% of episodes occurring during the first 3 months. The 30-day post-BSI mortality rate was 26% (95% confidence interval: 19-32) and BSIs were involved in 10% of early non-cancer deaths. The risk of BSI development is associated with several patient- and disease-related factors and BSIs contribute considerably to early non-cancer mortality. Empiric antibiotic treatment regimens should prioritise coverage for S. aureus when treating suspected systemic infection in this population.