Simple SummaryHepatocellular carcinoma (HCC) is the most common primary liver cancer, and despite best efforts to stratify patients recurrence remains a major issue. Our study attempted to identify what variables are involved in recurrence of HCC after resection and if they be used to stratify an individual patient’s risk of recurrence. We developed a simple-to-implement RESected Tumor Outcome and Recurrence (RESTORE) index comprising three commonly assessed variables: alpha-fetoprotein level, vascular invasion, and tumor burden. The RESTORE index was highly predictive of HCC recurrence risk after resection. The RESTORE index will help identify patients who would potentially benefit from more intensive post-resection surveillance or adjuvant therapeutics.Abstract: ImportanceAlthough many variables have been associated with increased risk of hepatocellular carcinoma (HCC) recurrence after resection, no simple-to-implement risk score has been developed to determine this post-resection risk.Objective:We aimed to identify risk factors for HCC recurrence and develop a risk score for predicting recurrence of HCC in patients who undergo resection with curative intent.Design:Single-center retrospective analysisSetting:Single-center tertiary care referral hospital (University of San Francisco, California).Participants:Patients who underwent resection with curative intent for HCC between January 2005 and May 2019 with complete pathologic findings and recorded follow up.Main Outcomes and Measures:Univariate and multivariate Cox regression analysis were used to identify independent risk factors for HCC recurrence. A multivariable Cox proportional-hazard regression model with listwise deletion was used to create a risk score.Results:A total of 179 patients were included in the study; 129 (72.9%) were men, and the median (IQR) age was 63 (57–67) years. Median alpha-fetoprotein (AFP) was 12.3 ng/mL at time of resection. Most patients (82%) had a single tumor nodule, and the mean aggregate nodule size was 6.75 cm; 28.4% had evidence of vascular invasion. On multivariable Cox proportional-hazards regression, AFP ≥1000 ng/mL, multinodularity, and vascular invasion were independently associated with HCC recurrence. The RESTORE index was created using stratified pre-operative AFP, vascular invasion, and the presence of a single lesion within or beyond Milan Criteria versus multiple lesions. The RESTORE index ranged from 0–9 (highest patient score was 8) and was highly predictive of HCC recurrence (C statistic 0.70). RESTORE could stratify 5-year post-resection HCC recurrence risk, ranging from less than 25% with a score of 0 to more than 80% with a score of 5–8.Conclusions and Relevance:The RESTORE index that we developed and validated is a simple-to-implement and novel risk score for patients undergoing resection for HCC and may help identify those who would benefit most from intensive surveillance strategies or adjuvant therapies.