<b><i>Background and Aims:</i></b> The aim of the present study is to evaluate a new index influenced by the balance between the immune system, α-fetoprotein (AFP), and lactate dehydrogenase (LDH) (RAPID index) as a prognostic factor in patients treated with sorafenib. <b><i>Methods:</i></b> This study was conducted on a training cohort of 159 hepatocellular carcinoma (HCC) patients and a validation cohort of 68 HCC patients treated with sorafenib. The RAPID index was calculated as neutrophil/lymphocyte count × LDH × AFP. <b><i>Results:</i></b> In the training cohort, the median overall survival (OS) was 23.2 months (95% CI 11–25) and 12.1 months (95% CI 9–15) for patients with a low (≤3,226) and high (&#x3e;3,226) RAPID index, respectively (ref. &#x3c;3,226, HR = 0.56, 95% CI 0.35–0.88, <i>p</i> = 0.017). Following adjustment for clinical covariates, multivariate analysis confirmed the RAPID index ≤3,226 versus &#x3e;3,226 (HR = 0.37, 95% CI 0.18–0.74, <i>p</i> = 0.0054) as an independent prognostic factor for OS. In the validation cohort, the median OS was 26.9 months (95% CI 17.6–26.9) and 7.0 months (95% CI 6.2–9.2) for patients with a low (≤ 3,226) and high (&#x3e;3,226) RAPID index, respectively (ref. &#x3c;3,226, HR = 0.19, 95% CI 0.10–0.36, <i>p</i> &#x3c; 0.0001). Performing the same multivariate analysis of the training cohort (AFP, Eastern Cooperative Oncology Group, aspartate aminotransferase, neutrophil, platelet, systemic inflammatory index and RAPID index), the RAPID index &#x3c;3,226 versus &#x3e;3,226 (HR = 3.86, 95% CI 1.45–10.29, <i>p</i> = 0.007) was found to be an independent prognostic factor for predicting OS. <b><i>Conclusion:</i></b> The low cost, easy assessment, and reproducibility of a full blood count make the RAPID index a promising tool for assessing HCC prognosis in future clinical practice.