PTENP1, a pseudogene of PTEN, was previously reported to be a tumour suppressor in some cancer types. However, there was no evidence for the biological function and expression of PTENP1 in head and neck squamous cell carcinoma (HNSCC). Here, we evaluated the function and clinical implications of PTENP1 in HNSCC. Using RT-PCR and quantitative real-time PCR (qRT-PCR), we found that the level of PTENP1 was reduced in HNSCC specimens compared with adjacent tissues. A decrease in the PTENP1 copy number, but not in the PTEN copy number, was frequently observed in tumour cell lines (4 of 5 cell lines) by genomic real-time PCR. Decreased PTENP1 expression was significantly associated with a history of alcohol use (P = 0.034). Univariate and multivariate Cox regression analyses revealed that low expression of PTENP1 correlated with worse overall survival (OS, P = 0.005; HR:0.170; Cl:0.049 to 0.590) and disease-free survival (DFS, P = 0.009; HR:0.195; Cl:0.057 to 0.664) rates of HNSCC patients. Furthermore, ectopic PTENP1 expression inhibited the proliferation, colony formation and migration of HNSCC cells and the growth of xenograft HNSCC tumours. These results demonstrate that PTENP1 might play an important role in the initiation and progression of HNSCC.