GOALS: To evaluate the clinical implication of splenic volume measured by computed tomography (CT) scan in hepatocellular carcinoma (HCC) patients undergoing percutaneous radiofrequency ablation (RFA). BACKGROUND: Splenomegaly is an important sign of portal hypertension and poor liver function in patients with advanced liver disease. But whether it could predict the prognosis of patients with HCC is still obscure. STUDY: We enrolled 161 treatment-naive HCC patients. Splenomegaly was defined as splenic volume >300 mL by CT scan and its impact on prognosis was analyzed. Moreover, noninvasive serum markers were validated to predict splenomegaly. RESULTS: A total of 78 patients were with splenomegaly, while the remaining 83 patients had normal splenic volume at the time of receiving RFA. After a median follow-up of 38.1±20.8 months, 41 patients died. The cumulative 5-year survival rates were 54.8% and 77.8% in patients with splenomegaly and in those with normal splenic volume, respectively (P=0.003). By multivariate analysis, age 65 years and older, serum albumin levels ≤3.5 g/dL, and splenic volume >300 mL were independent risk factors associated with poor overall survival after RFA. For predicting splenomegaly by noninvasive serum markers, platelet count yielded the highest area under the curve from corresponding receiver operating curves with a level of 0.868 at a cut-off value of 11,7000/mm. CONCLUSIONS: HCC patients with splenomegaly measured by CT scan have relatively poorer liver functional reserve than those with normal splenic volume. Splenomegaly is an independent risk factor predicting overall survival for patients with small HCC undergoing RFA.