Long-term submandibular duct obstruction is thought to cause irreversible atrophy and dysfunction of the submandibular gland. As an atrophic gland may be induced clinically by chronic or recurrent infection, it is generally removed surgically. However, the regenerative capacity of atrophic submandibular glands after long-term obstruction is not completely understood. We studied the regenerative capacity of the mouse submandibular duct using an aneurysm clip ligation model. We documented changes in the size, histologic structure and gene expression of the submandibular gland after 2 months of ligation, and 1 week, 1 month and 2 months after clip removal. Two months of ligation caused atrophy, particularly in the acinar portion. In the 2 months after clip removal, we observed a steady and significant increase in the expression of the acinar cell precursor gene cytokeratin 5 (CK5), and a significant decrease in the expression of the stem cell marker c-kit. These findings suggest that the submandibular gland retains some capacity for regeneration even after long-term obstruction, and that CK5 could serve as a marker of this regenerative process.