Background: Previous studies reported that inflammatory biomarkers could play a prognostic role in patients with unresectable hepatocellular Carcinoma (HCC) treated with sorafenib therapy, but there are no enough studies on new generations of systemic therapy. Objectives: The aim of this study was to evaluate dynamic changes of systemic inflamma-tory markers in patients with unresectable HCC on systemic therapy and to investigate their association with tumor behavior, drug hepatotoxic side effects and overall survival. Subjects and methods: This prospective study was carried out on 235 patients with unresectable HCC. Patients were divided into three groups based on type of systemic therapy: sorafenib group, atezolizumab-bevacizumab group, sequential TKI group (patients who received sorafenib then were shifted to regorafenib). CBC was followed up every month and the foll-owing ratios neutrophil/lymphocyte ratio (NLR), platelet/ lymphocyte ratio (PLR), monocyte count/lymphocyte count (MLR) and systemic inflammatory response index (SIRI) were calculated and analyzed. Results: A statistically sign-ificant increase in median MLR among Atezo-Bev group after 4 months (p=0.007) was observed, while among sorafenib group; MLR values increase significantly at 4, 8, 12 months (p < 0.001, 0.05, 0.029 respectively). SIRI decreases after 4 months within sequential TKI group (p=0.006) and after 20 months within sorafenib group (p=0.006). PLR was higher among cases with radiologic progression than those without in sorafenib group (P= 0.006), while within Atezo-Bev group; higher NLR was associated with radiologic progression (P= 0.024). Moreover, NLR was higher in patients who develop hepatotoxic side effects due to sorafenib, atezolizumab-bevacizumab (P= 0.04, 0.012 respectively). Conclusion: Systemic inflammatory response markers may offer prognostic value for an optimized selection of patients with HCC who may benefit more from systemic therapy