ABSTRACT Purpose: Using the unseeded technique of tissue engineering, small intestinal submucosa (SIS) has been shown to promote bladder regeneration. Initial studies using hand-made SIS obtained from sows demonstrated consistent and reliable results but since then surgical regenerative results have been inconsistent. SIS has been obtained from various sources and processed in different ways, thereby making it difficult to determine the single most important factor in obtaining reliable and consistent bladder regeneration using the unseeded technique. We review some of the previously used SIS materials, and compare SIS material made from the proximal small bowel to SIS made from the distal ileum. Materials and Methods: In a canine bladder augmentation model we directly compared SIS derived from proximal segments of jejunum to SIS derived from distal segments of ileum. All 6 animals underwent partial (40%) cystectomy and immediate augmentation with 1 of the 2 SIS materials. We assessed the harvested bladders for the amount of regeneration, SIS graft size and shrinkage 10 weeks after augmentation. Results: Both SIS materials demonstrated some evidence of bladder regeneration but it appeared that only sow age greater than 3 years) distal ileum SIS produced consistent bladder regeneration without bone formation and severe shrinkage. Conclusions: After years of SIS bladder regeneration research, it appears that not all material, even if obtained from different segments of 1 sow's bowel, has the same regenerative results. Therefore, the acronym SIS should be considered generic. Before clinical bladder augmentation further investigation is needed to identify the regenerative potential of specific SIS segments.