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Introduction Worldwide,~6 87 000 new cases of head and neck cancer are diagnosed annually with more than 3 80 000 deaths. Dysregulation of the tumour suppressor p53 is common in head and neck squamous cell carcinoma (HNSCC) especially in aggressive tumours. TP53 is mutated in 50%–80% of HNSCC but relatively little is understood about the biological and clinical impact of proto-oncogenes that regulate p53. Here, we show that proto-oncogenes pituitary tumour transforming gene 1 (PTTG) and its interacting partner PBF cooperate to regulate p53 activity in HNSCC. In addition, we probe TCGA data and reveal that PTTG and PBF represent new and useful prognostic indicators. Material and methods PTTG/PBF expression was determined in matched (tumour/normal) HNSCC tissue (n=24). p53 expression and function was assessed in 92-VU-040T [wild-type TP53 (wtTP53)] and 93-VU-147T [mutant TP53 (mTP53)] cells with lentiviral shRNA ablation of PTTG and PBF. Expression of PTTG, PBF and p53-target genes, as well as patient overall survival (OS), was analysed using HNSCC TCGA data. Results and discussions HNSCC tissue revealed significant upregulation of PTTG (1.9-fold, p Conclusion These findings provide compelling evidence that PTTG and PBF cooperate to dysregulate p53 in HNSCC which results in greater impairment of p53-dependent signalling and contributes towards worse clinical outcomes.