Background <p>Performance status (PS) plays a crucial role in prognostic prediction for patients with hepatocellular carcinoma (HCC). The extent of tumor burden is also a major survival determinant. Recently, tumor burden score (TBS) was proposed to evaluate the extent of tumor involvement, but the interaction between TBS and PS has not been evaluated. We aimed to assess the prognostic role of TBS in HCC patients with variable PS.</p> Methods <p>A large cohort of 4185 treatment-naïve HCC patients were retrospectively analyzed. The multivariate Cox proportional hazards model was used to determine the independent predictors associated with survival.</p> Results <p>Patients with poorer PS had significantly higher TBS at baseline. In the Cox model, older age, lower serum albumin level, higher serum bilirubin, creatinine and α-fetoprotein levels, presence of ascites, presence of vascular invasion, PS 1–2, PS 3–4, and medium TBS and high TBS were independently associated with increased mortality in the entire cohort (p &lt; 0.001). In subgroup analysis stratified by PS, TBS was able to predict long-term survival in patients with PS 0 in the multivariate model. For patients with PS 1–2, the trend was significant only in those with high TBS (p &lt; 0.001); in patients with PS 3–4, TBS was not significantly associated with survival (p &gt; 0.05).</p> Conclusions <p>TBS is a feasible prognostic surrogate for HCC and can well discriminate long-term survival in patients with good PS. Our findings demonstrate that TBS has a differential prognostic impact on HCC and may play a distinct role in outcome prediction for patients with variable PS.</p>