Abstract: Background　Both secretary carcinoma (SC) and acinic cell carcinoma (AciCC) of the salivary glands are lowgrade malignant tumors of epithelial origin. Due to the diversity of their histological morphology and cell types, which are extremely similar, there are certain difficulties and insufficient understanding in the differential diagnosis and prognosis judgment of these two types of tumors. Objective　To conduct a comparative study on the clinical and pathological features of AciCC and SC of salivary glands, aiming to provide accurate pathological diagnostic evidence for the clinical diagnosis and treatment of salivary gland AciCC and SC. Methods　Cases of salivary gland AciCC and SC diagnosed at the Department of Pathology, the First Medical Center of PLA General Hospital from September 2005 to September 2024 were retrospectively analyzed. The study encompassed clinicopathological and molecular data, including routine histology, immunohistochemistry, and molecular testing, along with prognostic follow-up to compare outcomes. Results　A total of 109 cases were included in this study, comprising 90 cases of salivary gland AciCC and 19 cases of SC. The mean age of the two groups was (44.0±17.7) years and (40.0±15.7) years, respectively, with a median age of 46 years in both groups. Regarding gender distribution, males accounted for 38.9% (35/90) in the AciCC group and 73.7% (14/19) in the SC group, and the difference between the two groups was statistically significant (P=0.006). In terms of tumor location, both types showed a predilection for the parotid gland, with parotid involvement observed in 85.6% (77/ 90) of AciCC cases and 89.5% (17/19) of SC cases. Conventional pathological examination revealed overlapping cytological and histological features between the two tumor types, both of which may present with tubular, solid, microcystic, or papillary structures. Immunohistochemical findings provided discriminative value, all SC cases exhibited diffuse and strong positivity for S-100, SOX10, and Mammaglobin, whereas none of the AciCC cases expressed these markers. Molecular pathology further supported the distinction, as the ETV6-NTRK3 fusion gene was detected in most of SC cases (68.4%, 13/19) but was absent in all AciCC cases. Survival analysis indicated that the median survival time was 72.5 months (95% CI: 78.7 - 107.8) in the AciCC group and 48.0 months (95% CI: 32.7 - 79.2) in the SC group. Log-rank test demonstrated a statistically significant difference in survival between the two groups (P=0.008). Conclusion　Salivary gland AciCC and SC exhibit distinct differences in gender distribution, immunophenotypes, molecular genetic profiles, and long-term survival patterns. Notably, the ETV6-NTRK3 fusion gene, which is consistently present in SC, serves not only as a key diagnostic marker but also represents a promising avenue for targeted therapy.