Appropriate DNA replication is vital to maintain cell integrity at the genomic level. Malfunction on DNA repair mechanisms can have implications related to tumor behavior. Our aim was to evaluate the expression of key complexes of the DNA mismatch-repair system MutS? (hMSH2-hMSH6) and MutS? (hMSH2-hMSH3) in a panel comprising the most common benign and malignant salivary gland tumors (SGT), and to determine their association with disease-free survival. Ten cases of normal salivary gland (NSG) and 92 of SGT (54 benign and 38 malignant) were retrieved. Immunohistochemistry was performed for hMSH2, hMSH3, hMSH6. Scanned slides were digitally analyzed based on the percentage of positive cells with nuclear staining. Cases were further classified in MutS?high and MutS?high based on hMSH2-hMSH6 and hMSH3-hMSH6 expression, respectively. hMSH3 expression was lower in malignant SGT compared to NSG and benign cases. Adenoid cystic carcinoma (ACC) cases with perineural invasion presented a lower percentage of hMSH3 positive cells. hMSH6 was downregulated in both benign and malignant SGT compared to NSG. Malignant SGT cases with MutS?high expression had lower disease-free survival compared to MutS?low cases. A 10.26-fold increased risk of presenting local recurrence was observed. Our findings suggest that a lack of hMSH3 protein function is associated with a more aggressive phenotype (malignancy and perineural invasion) and that MutS? overexpression predicts a poor clinical outcome in malignant SGT.