Background: The aim of this study was to investigate whether serum immune and inflammatory parameters can help to predict the clinical outcomes in patients with unresectable hepatocellular carcinoma (HCC) undergoing curative radiation therapy (RT). Methods: A total of 76 RT courses among 71 patients between January 2014 and April 2019 were analyzed. The following variables were included in the analysis: systemic inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), absolute lymphocyte count, lymphocyte-to-monocyte ratio (LMR), albumin, albumin-to-alkaline phosphatase ratio, RT-related parameters, and levels of total protein, hemoglobin, α-fetoprotein, PIVKA-II, and C-reactive protein. Overall survival (OS), local control (LC), distant control (DC), and intrahepatic control (IHC) rates were calculated using the Kaplan-Meier method, and graphs were compared using the log-rank test. The multivariate Cox model was used to identify independent prognostic factors. The optimal cutoff values for survival separation were decided using the maximal chi-square test. Results: The mean age was 61.4 years, and most patients were men (n = 62, 81.6%). Most of the study population underwent pre-RT TACE/HAIC (n = 74, 97.4%). The median RT fraction number, fractional doses, and biologically equivalent doses by α/β=10 were 12 (range, 4–30), 5 (range, 2–12) Gy and 72.6 (range, 51.5–119) Gy, respectively. With a median follow-up of 12 (range, 3.1–56.7) months, the 1-year OS, LC, DC, and IHC rates were 55.2%, 88.2%, 64.4%, and 50.5%, respectively. In the multivariate analysis, significant independent prognostic indicators were the lowest posttreatment PNI for OS (P< 0.001), lowest pretreatment LMR for LC (P = 0.03), and highest posttreatment PLR for DC (P = 0.006). Conclusions: Distinct serum-based parameters predicted OS, LC, and DC rates. Future research is necessary to confirm our findings.