Background: Sorafenib is the first systemic therapy approved for advanced HCC treatment; with no accurate tool available to help predict survival and treatment outcome and to guide therapy decisions. Our novel blood-based IGF-Child-Pugh (CP) score comprises levels of IGF-1, bilirubin, INR, and albumin. IGF-CP score significantly improved the prediction of HCC survival in our recently published studies. The current prospective study aimed to compare the overall survival (OS) and progression free survival (PFS) of 101 patients with CP-A HCC treated with sorafenib whose score is reclassified as IGF-A (AA) to that of patients whose score is reclassified as IGF-B/C (AB/AC). Methods: Between 2014 and 2018, after the approval of the institutional review boards and signing written informed consent, a total of 101 patients with HCC, CP-A were prospectively enrolled and started on sorafenib and followed until progression or death. Results: Sixty-three patients were evaluable. Patients who were reclassified by the IGF-CTP scoring system were better stratified by their new risk groups. Forty-two of patients were classified as IGF-CTP-A and had median PFS of 4.87 months (95% CI=2.3 to 6.84), and median OS of 15.43 (95% CI = 12.04 to 31.18 months), whereas 21 patients were reclassified as intermediate risk (IGF-CTP-B) and had significantly shorter OS of 7.6 months (p-value<0.0001) and shorter PFS of 2.86 months (p-value=0.0021). Conclusions: The results of this study confirms our biologically driven hypothesis that: among HCC patients with “old CP-A” class treated with sorafenib, some will be reclassified as “new CP-B/C” will have poorer prognosis in terms of shorter OS and PFS. Thus, our study provides an objective non-invasive strategy to better predict the outcome in HCC patients undergoing systemic therapy. Future validation of our IGF score may lead to adopting it as a stratification tool in trials to predict HCC outcome and guide therapy decision in routine practice.