Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is a mitochondrial inner membrane protein and plays an important role in mitochondrial ATP production and biogenesis. High expression levels of LETM1 have been correlated with numerous human malignancies. This study explored the clinicopathological significance of LETM1 expression as a prognostic determinant in head and neck squamous cell carcinoma (HNSCC). HNSCC samples from 176 patients were selected for immunohistochemical staining of LETM1 protein. Correlations between LETM1 overexpression and clinicopathological features of HNSCC were evaluated by Chi-squared tests and Fisher’s exact tests, and relationships between prognostic factors and patient survival were analyzed using Cox proportional hazards models. Our results demonstrated that the strongly positive rate of LETM1 protein was 65.3% in HNSCC, which was significantly higher than in either adjacent nontumor tissue (25.0%) or normal squamous epithelia (6.7%). LETM1 overexpression correlated with poor differentiation, presence of lymph node metastasis, advanced stage, absence of chemoradiotherapy, and 5-year disease-free survival and overall survival rates in HNSCC. Further analysis showed that high LETM1 expression, advanced stage, and nonchemoradiotherapy were significant independent risk factors for mortality in HNSCC. In conclusion, LETM1 plays an important role in the progression of HNSCC and is an independent poor prognostic factor for HNSCC.