Background To investigate the clinical efficacy of high-intensity focused ultrasound (HIFU) combined with transcatheter arterial chemoembolization (TACE) in the treatment of primary liver cancer (PLC) and its effect on the prognosis of patients. Methods A total of 132 patients with PLC admitted to our hospital were selected for the study, among whom 68 patients received TACE combined with HIUF and were assigned to the observation group (OG), whereas the remaining 54 patients were treated with TACE alone and were assigned to the control group (CG). The factors influencing the patients' prognosis were also evaluated by multivariate analysis. Results The total effective rate of the OG was 83.82%, which was significantly higher than that of 55.56% of the CG (P < .05). No significant difference was found in incidence of adverse reactions between the two groups (P > .05). After treatment, the increases of CD3+, CD4+, CD4+/CD8+, and NK cells in the OG were more significant than those in the CG (P < .05). However, the decrease of CD8+ cells was more significant in the OG than that in the CG (P < .05). The 3-year survival rate of patients in the OG was 61.76%, which was significantly higher than that of 40.74% in the CG (P < .05). Conclusion The application of TACE combined with HIFU is effective in treating PLC, which can prolong the life expectancy and improve the prognosis of patients with PLC without increasing the incidence of adverse reactions.