Objectives:To evaluate the clinical efficacy of highly agglutinative staphylococcin combined with neoadjuvant chemotherapy on patients with intermediate or advanced oral cancer.Methods:A total of 80 patients with intermediate or advanced oral cancer treated in Affiliated People’s Hospital of Fujian University of Traditional Chinese Medicine from January 2020 to January 2022 were included. Patients were divided into two groups based on their treatment choice, with 40 cases in each group. Patients in the control group were given paclitaxel combined with cisplatin chemotherapy regimen: paclitaxel 150 mg/m2 and cisplatin 100 mg/m2 on Day-1, with 28 days as one cycle of chemotherapy for a total of three cycles. Patients in the experimental group received intramuscular injection of 500U highly agglutinative staphylococcin once a day for two weeks on the basis of chemotherapy, and continued the next course of treatment after 1 week of withdrawal, with a total of two courses. After treatment, the therapeutic effect, adverse drug reactions, changes in tumor markers such as CEA, NSE, CA19-9 and CA125 before and after treatment, as well as differences in levels of CD3+, CD4+, CD8+ and CD4+/CD8+ of T lymphocyte subsets between the two groups before and after treatment were compared and analyzed.Results:The total efficacy of the experimental group was 80%, which was significantly better than 57.5% of the control group (P=0.03). The incidence of adverse drug reactions in the experimental group was 17.5%, while that in the control group was 42.5%, showing a statistically significant difference (P=0.02), and the WBC count decreased more significantly in the control group (P=0.04). CEA, NSE, CA19-9 and CA125 decreased significantly in the experimental group after treatment compared with the control group, with a statistically significant difference (P=0.00). Moreover, the levels of CD3+, CD4+, CD4+/CD8+ in the experimental group after treatment were significantly higher than those in the control group, with statistically significant differences (CD3+, P=0.03; CD4+, P=0.00; CD4+/CD8+, P=0.00), while CD8+ did not change significantly (P=0.95).Conclusions:Highly agglutinative staphylococcin combined with chemotherapy is a safe and effective treatment regimen with definite curative effect for patients with intermediate or advanced oral cancer. With such a regimen, tumor markers are remarkably reduced, immune function can be significantly improved, and adverse reactions will be evidently reduced.