Adenoid cystic carcinoma (ACC) of the salivary gland is generally an indolent tumor that pursues a protracted clinical course with recurrences and late metastasis. The authors report three cases of ACC with dedifferentiation to high-grade malignant neoplasms. One patient developed dedifferentiated ACC ab initio, with extensive local disease and multiple lymph nodes metastases at first presentation, requiring mutilating surgery. Two patients had dedifferentiated ACC 4 and 10 years, respectively, following excision of the initial uncomplicated ACC; both patients died within 1.5 years after recurrence. Histologically, the dedifferentiated component appeared as a distinct population of anaplastic cells with more abundant cytoplasm, irregular-shaped tumor islands infiltrating a desmoplastic stroma, and total loss of bicellular differentiation characteristic of ACC. The immunophenotypic profile was altered in comparison with the ACC, such as acquisition of strong staining for S100 protein and lack of a myoepithelial component in the two cases that were interpreted as being poorly differentiated adenocarcinoma. One case was a sarcomatoid neoplasm with focal myoepithelial features. Overexpression of p53 protein was demonstrated in the dedifferentiated component in one case, and overexpression of cyclin D1 was seen in two cases. The dedifferentiated component had a higher Ki67 index than did the ACC. To the authors' best knowledge, this report represents the first documentation of dedifferentiation as a form of tumor progression in ACC, which is associated with a sinister clinical outcome.