For patients diagnosed with hepatocellular carcinoma (HCC) not eligible for surgical tumor resection, transarterial chemoembolization (TACE) is commonly employed as a therapeutic strategy. After TACE is complete, a variety of other therapeutic approaches can be employed to improve patient overall survival (OS) and progression-free survival (PFS). This study was developed with the goal of comparing the relative clinical efficacy and long-term outcomes observed in HCC patients who underwent combination TACE and radioactive seed insertion (RSI) treatment to those of patients who only underwent TACE treatment. This retrospective analysis included a total of 80 patients with HCC who underwent treatment via TACE with (n = 39) or without (n = 41) RSI. Treatment responses and long-term outcomes in these two groups were compared with one another. The baseline characteristics of both groups were comparable. None of the patients experienced adverse complications related to treatment. Individuals in the combination treatment group experienced complete response (59.0% vs. 22.0%, p = 0.001) and total response (92.3% vs. 58.5%, p = 0.001) rates that were significantly better than those of patients that underwent TACE alone. Combination treatment was also associated with significant prolongation of patient PFS (13 vs. 7 months, p = 0.019) and OS (23 vs. 15 months, p = 0.005), with Cox regression analyses identifying combination treatment as a predictor of prolonged PFS and OS. These data suggest that a combination of TACE and RSI can contribute to significant improvements in HCC patient therapeutic response rates, OS, and PFS relative to TACE alone.