Present work was inspired by an interesting finding of Raithel et al. (11) about remission of steroid-dependent, chronically active ulcerative colitis (UC) in a patient, after treatment with a combination of fexofenadine, disodium cromoglycate and an amino acid-based formula. Literature reports involvement of mast cells activation and increased histamine secretion in the pathogenesis of colitis. The purpose of present work was to evaluate the potential of a novel prodrug of fexofenadine in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. A colon-specific mutual amide prodrug of fexofenadine with D-glucosamine was synthesized. Release was studied in tissue homogenates and rat fecal matter by HPLC. It was further screened in TNBS-induced colitis in rats and also for adverse effects on rat liver, stomach and pancreas. The spectral analysis confirmed the structure of the prodrug. Highly hydrophilic prodrug enabled efficient delivery of fexofenadine to colon. Prodrug furnished negligible release of fexofenadine in upper gastrointestinal tract (GIT) homogenates. About 82% release of fexofenadine was observed in rat fecal matter at the end of 12 hours. The prodrug was twice as effective in lowering the quantifying parameters of colonic inflammation in TNBS- induced colitis than fexofenadine, D-glucosamine, their physical mixture and interestingly oral 5-amino salicylic acid while 2.7 times less effective than sulfasalazine. The prodrug restored disrupted colonic architecture to normal without adversely affecting stomach, liver and pancreas. In conclusion, the results support histamine involvement in the pathogenesis of UC. This novel, dual acting colon-specific prodrug of fexofenadine is promising as combination maintenance therapy with sulfasalazine for UC.