A rabbit model was used for the evaluation of a collagen-based biomatrix of small intestinal submucosa (SIS, COOK) in comparison to a biochemically reconstructed biomatrix for bladder tissue regeneration. Rabbits underwent partial cystectomy and cystoplasty with SIS patch graft or with a biochemically defined collagen biomatrix. The grafts of the regenerated bladder wall were harvested at different intervals and tissue regeneration was evaluated. The results of the SIS and biochemically defined biomatrix grafts were comparable. At harvesting, we found five bladder stones and encrustation of the biomatrix in 21/56 animals. No stone formation was observed in the control group. The results of the molecularly defined biomatrix are thus far comparable to SIS. Both matrices show good epithelialization and ingrowth of smooth muscle cells. Both biomatrices show considerable encrustation, which appears to disappear in time. The rabbit model is suitable for bladder tissue engineering studies as it is an easy model to use. In this model, besides tissue regeneration, also some of the clinical problems are seen such as encrustation of foreign body material in the bladder. These aspects are subject for further pre-clinical studies in this animal model.