Small intestinal submucosa (SIS) is a biodegradable scaffold that supports bladder regeneration after partial cystectomy. We sought to define the inflammatory response present in a rat bladder augmentation model using distal ileal SIS. Fifteen Sprague-Dawley rats underwent hemi-cystectomy followed by anastomosis of a bladder patch of SIS. Bladders were excised after days 2, 7, 14, 28, and 56. Tissue regeneration was evaluated by standard hematoxylin and eosin. Immunohistochemical staining was used to quantify neutrophils, macrophages, eosinophils, and mast cells. Total cell counts per unit area were compared between native and graft portions of the bladder for each cell type across the entire time course. Statistical analyses were conducted with the Wilcoxon Rank-Sum and Kruskal-Wallis tests. All tests were two-sided with significance set at p < 0.05. These inflammatory responses evolved consistently across all bladders over time. Neutrophil and eosinophil numbers were highest at day 2 and decreased over the 56-day period. In contrast, macrophage and mast cell numbers were low at days 2, 7, and 14; peaked at day 28; and decreased once again at day 56. Cell counts at native and graft sites were equivalent for all cell types, except neutrophils, which were more commonly found in the graft (124 vs. 24 cells/mm(2), p = 0.009). Thus, the inflammatory processes change over time during SIS-mediated bladder regeneration. Similar cell densities are present between the native and SIS portions of the bladder, but neutrophils predominate in the graft areas.