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Objectives: Post-hepatectomy liver failure (PHLF) can occur as a major complication after hepatic resection (HR) in patients with hepatocellular carcinoma (HCC) and negatively affects the prognosis. We aimed to retrospectively assess whether the spleen volume (SV) measured from preoperative CT images would be associated with the development of PHLF and overall survival (OS) after HR in patients with HCC. Methods: We enrolled 317 consecutive patients with very early/early stage HCC who underwent a preoperative CT and HR between January 2010 and December 2016. The SV was obtained from preoperative CT images using semi-automated volumetric software and was divided by body surface area to yield SVBSA. Receiver operating characteristic (ROC) curves and logistic regression analyses were performed to identify factors affecting the development of PHLF. The Cox proportional hazard model was used to identify prognostic factors for OS. Results: PHLF was observed in 72 patients (22.7% [72/317]). SVBSA was associated with the development of PHLF (odds ratio, 2.321; 95% CI, 1.347–4.001; p = 0.002) with the area under the ROC curve of 0.663 using the cutoff value of 107.5 cm3 (p < 0.001). SVBSA was also an influencing factor for OS (hazard ratio, 3.935; 95% CI 1.520–10.184; p = 0.005), with the optimal cutoff of 146 cm3. The 5-year OS rate was higher in 245 patients with a SVBSA ≤ 146 cm3 than in 72 patients with a SVBSA > 146 cm3 (95.0% vs. 78.7%, p < 0.001). Conclusions: In patients with HCC, a larger SVBSA was associated with a higher rate of PHLF and worse OS after HR. The SVBSA may be useful in selecting good surgical candidates. Key Points: • A significantly higher spleen volume divided by body surface area was observed in patients who experienced post-hepatectomy liver failure than in patients who did not (148 cm3vs. 112 cm3, p < 0.001). • The area under the receiver operating characteristic curve of spleen volume divided by body surface area to predict the development of post-hepatectomy liver failure was 0.663 (p < 0.001). • Spleen volume divided by body surface area was a significant influencing factor for overall survival (hazard ratio, 3.935; 95% CI, 1.520–10.184; p < 0.001), with the optimal cutoff of 146 cm3. [ABSTRACT FROM AUTHOR]