Background Targeted and Immunotherapy has emerged as a new first-line treatment for advanced hepatocellular carcinoma (aHCC). To identify the appropriate targeted and immunotherapy, we implemented next generation sequencing (NGS) to provide predictive and prognostic values for aHCC patients. Methods Pretreatment samples from 127 HCC patients were examined for genomic changes using 680-gene NGS, and PD-L1 expression was detected by immunohistochemistry. Demographic and treatment data were included for analyses of links among treatment outcomes, drug responses, and genetic profiles. A prognostic index model for predicting benefit from treatment was constructed, taking into account of biomarkers, including TP53, TERT, PD-L1, and tumor mutation burden (TMB) as possible independent prognostic factors. Results The multivariate Cox regression analyses showed that PD-L1 >= 1% (HR 25.07, 95%CI 1.56 - 403.29, p=0.023), TMB >= 5Mb (HR 86.67, 95% CI 4.00 - 1876.48, p=0.004), TERT MU (HR 84.09, 95% CI 5.23 - 1352.70, p=0.002) and TP53 WT (HR 0.01, 95%CI 0.00 - 0.47, p=0.022) were independent risk factors for overall survival (OS), even after adjusting for various confounders. A prognostic nomogram for OS was developed, with an area under the ROC curve of 0.91, 0.85, and 0.98 at 1-, 2-, and 3- year, respectively, and a prognostic index cutoff of 1.2. According to the cutoff value, the patients were divided into the high-risk group (n=29) and low-risk group (n=98). The benefit of targeted and immunotherapy in the low-risk group was not distinguishable according to types of agents. However, treatment of Atezolizumab and Bevacizumab appeared to provide longer OS in the high-risk group (12 months vs 9.2, 9, or 5 months for other treatments, p<0.001). Conclusion The prognostic model constructed by PD-L1, TMB, TERT, and TP53 can identify aHCC patients who would benefit from targeted and immunotherapy, providing insights for the personalized treatment of HCC.