To investigate the short and long term histopathological alterations caused by submucosal injection of dextranomers in sodium hyaluronan (DiHA) based on an experimental rat model. Sixty Sprague-Dawley rats were assigned into two groups as group I and II, each containing 30 rats. Totally 0.1 ml of saline solution and 0.1 ml of DiHA were injected into the submucosa of bladder of first (control) and second groups, respectively. Both group I and II were further subdivided into three other groups as Group IA, IB, IC and Group IIA, IIB, IIC according to the sacrificial period. Group IA and IIA, IB and IIB, IC and IIC rats (ten rats for each group) were sacrificed 3, 6, and 12 months after surgical procedure, respectively. Two slides prepared from injection site of the bladder were evaluated completely for each rat by being unaware of the groups and at random by two independent senior pathologists to determine the fibroblast invasion, collagen formation, capillary growth and inflammatory reaction. Additionally, randomized brain sections from each rat were also examined to detect migration of the injection material. The measurements were made using an ocular micrometer at 10x magnification. The results were assessed using t-tests for paired and independent samples, with P < 0.05 considered to indicate significant differences; all values were presented as the mean (SD). Migration to the brain was not detected in any group. Significant histopathological changes in the DiHA injected groups were granuloma formation in 43.3%, foreign body type giant cells in 76.6%, inflammatory infiltration in 100%, and fibroblasts surrounding microspheres in 100% of the rat bladder. The interaction between granuloma formation and long-term tissue effects in children is still obscure. We emphasize that further prospective human (and/or animal) studies are required to clarify the long-term effects of granuloma formation with regard to clinical applications.