Abstract: Objective: To investigate the clinical effi cacy of transcatheter arterial chemo e mb o l i z a t ion (TACE) sequential microwave ablation (MWA) combined with lenvatinib in the treatment of primary liver cancer and its eff ects on immune function and vascular endothelial growth factor (VEGF) level. Methods A retrospective analysis was conducted on the data of 100 patients with primary liver cancer admitted to Tangshan People’s Hospital from August 2020 to June 2022. According to diff erent treatment methods, the patients were divided into sequential group (49 cases) and study group (51 cases). Patients in sequential group were treated with TACE sequential MWA and patients in study group were treated with lenvatinib in addition on the basis of those in sequential group. The short-term effi cacy, immune function indicators (CD3+, CD4+, CD4+/CD8+), VEGF level, alpha-fetoprotein (AFP) level, incidence of adverse events and long-term survival outcomes were compared between the two groups of patients. Results The objective response rate of patients in study group was 82.35% (42/51), which was significantly higher than that of sequential group at 63.27% (31/49), and the difference was statistically signifi cant (χ 2 = 4.619, P = 0.032). Three months after treatment, the levels of CD3+ [sequential group: (61.29 ± 7.56)% vs. (50.86 ± 8.04)%; study group: (67.05 ± 6.71)% vs. (51.49 ± 8.35)%], CD4+ [sequential group: (36.45 ± 5.19)% vs. (29.36 ± 3.21)%; study group: (40.28 ± 5.33)% vs. (29.84 ± 3.47)%] and CD4+/CD8+ (sequential group: 1.21 ± 0.38 vs. 0.98 ± 0.32; study group: 1.39 ± 0.41 vs. 1.06 ± 0.35) in both groups were signifi cantly higher than their respective baseline levels before treatment (all P ＜ 0.05). All the above indicators in study group were signifi cantly higher than those in sequential group, and the diff erences were all statistically signifi cant (all P ＜ 0.05). Three months after treatment, the levels of VEGF [sequential group: (283.46 ± 35.14) ng/L vs. (429.41 ± 47.08) ng/L; study group: (236.81 ± 32.56) ng/L vs. (431.79 ± 48.42) ng/L] and AFP [sequential group: (103.38 ± 17.51) μg/L vs. (281.96 ± 32.46) μg/L; study group: (84.29 ± 15.72) μg/L vs. (284.17 ± 34.53) μg/L] in both groups were signifi cantly lower than respective baseline levels before treatment (all P ＜ 0.05). The above two indicators in study group were signifi cantly lower than those in sequential group, and the differences were both statistically significant (both P ＜ 0.05). There were no statistically signifi cant diff erences in the incidence of adverse events between the study group and sequential group, covering liver region pain (23.53% vs. 26.53%), abnormal liver function (35.29% vs. 32.65%), gastrointestinal reactions (43.14% vs. 38.78%), fever (15.69% vs. 18.37%), hypertension (9.80% vs. 2.04%), and leukopenia (13.73% vs. 10.20%) (all P ＞ 0.05). All the above adverse events were relieved after symptomatic management. The 2-year overall survival rate of patients in study group was 64.71% (33/51), which was significantly higher than that of 42.86% (21/49) in sequential group, and the difference was statistically significant (Log-rank χ 2 = 6.423, P = 0.011). Conclusions The combined use of TACE sequential MWA plus lenvatinib delivered favorable clinical effi cacy in patients with primary liver cancer. This combination strategy could not only effectively downregulate VEGF level and reduce the expression of the tumor biomarker AFP, but also signifi cantly improve the cellular immune function of patients, thereby remarkably increasing the objective response rate and 2-year survival rate, without a notable elevation in the incidence of adverse events.