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Background The size and number of tumors are important prognostic indicators for hepatocellular carcinoma (HCC). However, it is difficult to assess the prognosis for patients with a variable number and size of tumors. By combining these two factors, we investigated the role and prognostic accuracy of total tumor volume (TTV) for HCC. Methods A total of 786 patients undergoing locoregional therapy (transarterial chemoembolization, percutaneous radiofrequency ablation and acetic acid or ethanol injection) for HCC were prospectively evaluated. Results The mean and median TTV was 177 cm3 (range, 0.1-3,591 cm3) and 21 cm3, respectively. Of all, 38%, 29%, 15%, 7% and 11% of patients had TTV of 3, 10-50 cm3, 50-200 cm3, 200-500 cm3 and >500 cm3, respectively. TTV was significantly larger in patients with higher serum α-fetoprotein (AFP) levels or with vascular invasion. The Child-Turcotte-Pugh score, performance status, vascular invasion, AFP level and TTV were significant independent prognostic predictors in the Cox proportional hazards model. After adjustment, patients with TTV 50-200 cm3 (relative risk [RR]: 1.74, p = 0.009), 200-500 cm3 (RR: 2.15, p = 0.006) and >500 cm3 (RR: 3.92, p < 0.001) had a significantly increased mortality risk in comparison to patients with TTV 3. Conclusions TTV is a feasible prognostic predictor across a wide gradient and can be used to predict the mortality risk of HCC. Selecting appropriate cutoffs of TTV may help refine the design of cancer staging system and treatment planning. Future clinical trials of HCC may include this parameter for mortality risk stratification.