OBJECTIVE/HYPOTHESIS: Mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC), the most common malignancies of the major salivary glands, are clinically and pathologically different. To determine whether MEC and ACC have different molecular characteristics, we examined the expression of erbB-2, erbB-3, epidermal growth factor receptor (EGFR), and transforming growth factor-alpha (TGF-alpha), important molecular features in other malignancies. STUDY DESIGN/METHODS: Archival tissue sections of 22 MEC and 6 ACC tumors of the major salivary glands were evaluated immunohistochemically for expression of erbB-2, erbB-3, EGRF, and TGF-alpha. A differential immunostaining score, reflecting the difference in immunostaining between carcinoma and uninvolved salivary gland tissue, was calculated for cytoplasmic and membranous staining. RESULTS: Positive immunostaining for all biomarkers was observed in the cytoplasm and membrane of both tumors. However, expression was higher in MEC than in ACC tumors and was statistically significant for cytoplasmic EGFR (P =.009), TGF-alpha (P =.041), and membranous EGFR (P =.004). A significantly higher percentage of MEC cells also demonstrated positive immunostaining for cytoplasmic erbB-3 (P =.022), EGFR (P =.005), membranous erbB-3 (P =.022), and EGFR (P =.013). The differential immunostaining score was significantly higher for MEC compared with uninvolved alveolar tissue and the membranes of uninvolved ductal tissue. There were no statistically positive differential immunostaining scores for ACC. CONCLUSIONS: There is a clear difference in the molecular phenotypes of MEC and ACC. The lack of statistically significant expression in ACC, when compared with similar uninvolved salivary gland tissue, suggests minimal involvement for these molecular structures in the pathogenesis of ACC. Conversely, erbB-2, erbB-3, EGFR, and TGF-alpha may have a role in the development and progression of MEC. These results have therapeutic implications for MEC of the major salivary glands.