Abstract Aims There is an increasing incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell cancers (OPSCC) mostly associated with favourable outcomes. p16 immunohistochemistry is a surrogate marker for HPV positivity in OPSCC. The prognostic strength of p16 over traditional prognostic factors is not fully characterised. In this study, we evaluated the clinical and demographic differences between p16-positive and -negative OPSCC and characterised its prognostic strength versus traditional prognostic factors. Materials and methods Formalin-fixed, paraffin-embedded blocks and clinical information from 217 OPSCC patients, treated with radiotherapy (alone or in combination with other therapies) between 2000 and 2010 were collected retrospectively. Immunohistochemistry for p16 protein was carried out; cancer-specific survival (CSS), recurrence-free survival (RFS) and locoregional control (LRC) were calculated for both univariate and multivariate analyses. Results Ninety-two per cent of the OPSCC originated from tonsil and tongue base sites, 61% were p16 positive. Patients with p16-positive OPSCC were younger ( P  < 0.0001), with lower alcohol ( P  = 0.0002) and tobacco ( P  = 0.0001) exposure. The tumours were less differentiated ( P  = 0.0069), had a lower T stage ( P  = 0.0027), higher nodal status ( P  = 0.014) and higher American Joint Committee on Cancer (AJCC) prognostic group ( P  = 0.0036). AJCC prognostic group was significant for RFS ( P  = 0.0096) and CSS ( P  = 0.018) in patients with p16-negative OPSCC, but not those with p16-positive tumours ( P  = 0.30 and 0.54). Other significant factors for CSS and RFS in univariate analysis were: pretreatment haemoglobin ( P  < 0.0001 and <0.0001), chemoradiotherapy ( P  = 0.005 and 0.03) and P16 status ( P  < 0.0001 and 0.0001). In multivariate analysis, p16 positivity was the strongest independent prognostic variable for both CSS, RFS and LRC ( P  < 0.0001, hazard ratio 4.15; 95% confidence interval 2.43–7.08), ( P  < 0.0001, hazard ratio 6.15; 95% confidence interval 3.57–10.61) and ( P  = 0.001, hazard ratio 3.74; confidence interval 1.76–7.95). Conclusion This study shows that p16 is the single most important prognostic variable in OPSCC, surpassing traditional prognostic factors for both CSS and RFS. Furthermore, disease stage has no prognostic significance in p16-positive patients, highlighting the need for routine p16 assessment in OPSCC.