Background Hepatocellular carcinoma (HCC) is one of the most common cancers of the gastrointestinal tract worldwide. In Egypt, it is the leading cause of cancer-related mortality and morbidity. Sorafenib has been the treatment of choice for patients with advanced HCC since 2008. Currently, no specific biomarker has proven successful in predicting sorafenib efficacy. Inflammation is believed to be one of the drivers of cancer progression and metastasis development. The systemic immune inflammation index (SII) has been identified as a predictor for the outcome of cancer patients. Nutritional status appears to influence outcomes in various solid tumors. The Prognostic Nutritional Index (PNI) was introduced to assess the immune nutritional status of cancer patients. The aim of our study was to evaluate the prognostic and predictive value of SII and PNI in sorafenib-treated patients with advanced HCCMethod: This prospective, non-randomized study aimed to evaluate the prognostic value of SII and PNI in patients with advanced hepatocellular carcinoma (HCC) receiving sorafenib. One hundred and ten patients were included. Results The optimal cutoff values for PNI and SII using the Receiver Operating Characteristic (ROC) curve were 47.6 and 278, respectively. PNI and SII were significantly associated with disease control rate. Multivariate analyzes showed that low PNI and high SII were independent predictors of poor progression-free and overall survival. Conclusions There is cumulative evidence supporting the utility of pre-treatment PNI and SII as prognostic factors in sorafenib-treated HCC patients.