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Abstract: Background: Tumor volume in head and neck squamous cell carcinoma (HNSCC) was mainly measured in nonsurgically treated patients. We analyzed the influence of tumor volume on complete response (CR), overall survival (OS), and clear surgical margins also in primarily surgically treated patients. Methods: In contrast‐enhanced CTs, the tumor volumes of patients with incident HNSCC were measured. Results: The tumor volumes of 259 patients were measured, of which 125 patients (48%) underwent primary surgery and 102 patients (84%) had clear margins. The tumor volume was not an independent factor for CR at the primary tumor site. Risk of death increased by 1.4% per mL of tumor volume (95% confidence interval [CI] 0.8%‐2.0%; P < .001). The OS was better in patients treated with primary surgery, if the tumor volume was ≤12 mL (P < .001). Risk of involved margins increased by 4.5% per mL of tumor volume (95% CI 0.9%‐8.3%; P = .003). The predicted probability of clear margins was ≥80% in tumor volumes ≤ 16 mL. Conclusion: The tumor volume had an impact on CR, OS, and clear margins. The tumor volume may also aid in selecting HNSCC treatment. [ABSTRACT FROM AUTHOR]