We assessed the expression and the prognostic role of lactate dehydrogenase 5 (LDH5, the major LDH isoenzyme involved in anaerobic glycolysis) in patients with squamous cell head and neck cancer (SCHNC). LDH5 was assessed immunohistochemically in whole tissue sections from 141 patients with SCHNC. Of these, 102 were subjected to surgery with (90 patients) or without (12 patients) postoperative radiotherapy (group A), while 39 patients were treated with radical radiotherapy (group B). Mixed nuclear/cytoplasmic LDH5 expression was detected in 72.5% of group A and 61.5% of group B patients. This was significantly related to T4-stage (p= 0.04) and hypoxia-inducible factor-1α (HIF-1α) expression (p= 0.002). In group A, high LDH5 was linked with poorer distant metastasis-free survival (p= 0.01) and disease-specific overall survival (OS; p= 0.009). In multivariate analysis, LDH5 (p= 0.002) and HIF-1α (p= 0.01) were independently linked with distant metastasis. LDH5 was also linked with death events (p= 0.005). In group B, high LDH5 expression was significantly associated with poorer local relapse-free survival (p= 0.009) and OS (p= 0.01). In multivariate analysis, only T stage was a significant predictor of death events (p= 0.04). LDH5 is highly expressed in SCHNC and is linked with local relapse, survival and distant metastasis, suggesting that LDH5 is a marker of radioresistance and a target for therapeutic interventions.