AbstractMucoepidermoid carcinoma (MEC) of the breast is an extremely rare salivary gland‐type tumor characterized by epidermoid, basaloid, intermediate, and/or mucinous cells arranged in solid and cystic patterns. Despite their triple‐negative phenotype, breast MECs are generally considered low‐risk malignancies but their biology is largely unexplored; therefore, guidelines for clinical management are lacking. Here, we sought to characterize the molecular landscape of breast MECs. Thirteen cases were histologically reviewed, characterized for tumor‐infiltrating lymphocytes (TILs), and were subjected to immunohistochemistry for programmed death‐ligand 1 (PD‐L1, clone 22C3), EGFR, and amphiregulin (AREG). Rearrangements inMAML2andEWSR1were investigated by fluorescent in situ hybridization. Targeted next‐generation sequencing of 161 genes was performed on eight cases. Most MECs had low histological grade (n= 10, 77%), with the presence of TILs (n= 9/12; 75%) and PD‐L1 combined positive score ranging from 10 to 20 (n= 4/6; 67%). All cases showed EGFR and AREG overexpression and were fusion negative. Enrichment of genetic alterations was observed in PI3K/AKT/mTOR and cell cycle regulation pathways, while only one case harboredTP53mutations. This is the first study providing extensive molecular data on breast MECs and the largest collection of cases available to date in the literature. Breast MECs lackTP53mutations found in high‐grade forms of triple‐negative breast cancers andMAML2orEWSR1rearrangements pathognomonic of salivary MECs. Triple‐negativity and PD‐L1 positivity suggest a window of opportunity for immunotherapy in these patients. The EGFR/AREG axis activation, coupled with the mutational patterns in PI3K/AKT/mTOR and cell cycle pathways warrants caution in considering MECs as low‐risk neoplasms.