Salivary duct carcinoma (SDC) is an infrequent, aggressive tumor with a histologic similarity to ductal breast carcinoma. It must be differentiated from breast metastasis and other high-grade salivary tumors with glandular differentiation. Its histologic similarity to breast carcinoma raises the possibility that hormonal manipulation might also be of use in its treatment. Little is known concerning its pathogenesis. Expression of variant isoforms of CD44, a transmembrane molecule involved in cell-matrix interactions, confers metastatic potential on carcinoma cells in animal models and might also be important in the clinical progression of some human tumors. To address these diagnostic, therapeutic and pathogenetic issues, we performed an immunohistologic study on formalin-fixed, paraffin-embedded sections of 12 SDCs (7 from men, 5 from women), using antibodies to androgen receptor (AR), estrogen receptor (ER), progesterone receptor (PR), gross cystic disease fluid protein (GCDFP-15), CD44s, and CD44v6. A mucicarmine stain was also performed in each case. Luminal and focal intracellular mucin positivity was observed in 11 of the 12 tumors. There was strong, diffuse reactivity for AR in 11 of 12 and of GCDFP-15 in 12 of 12, and nonreactivity for ER and PR in 12 of 12. CD44s was negative (9 of 12) or only focally positive (3 of 12), and CD44v6 was diffusely positive in 12 of 12. Our study shows that most SDCs have luminal and focal intracellular mucin; that the immunophenotype AR+/ER-/PR-/GCDFP+ in a malignant salivary tumor with an intraductal (in situ) pattern is characteristic of SDC but does not completely exclude metastasis from the breast, which might also be AR+ and ER/PR- in a lesser proportion of cases; that enhanced expression of CD 44v6 might be an indication of its link to tumorigenesis; and that uniform AR expression raises the possibility that antiandrogen therapy might have a role in the management of patients with disseminated disease.