Ulcerative colitis (UC) is a chronic inflammatory autoimmune disease with limited treatment modalities. The animal model of colitis induced by treatment with trinitrobenzene sulfonic acid (TNBS-colitis) is commonly used to test new therapies of this disease. In our previous work we found that epicutaneous (EC) immunization with protein antigen induced a state of profound immunosuppression that inhibited inflammatory response in contact sensitivity, in experimental autoimmune encephalomyelitis (EAE) and in allogeneic skin graft rejection. TNBS-induced colitis was used as an experimental model. In our current work, we showed that EC immunization with TNP-conjugated mouse immunoglobulin (TNP-Ig) prior to induction of TNBS-colitis alleviates disease severity what was determined by the body weight, the length and the weight of the colon, the histological activity index (HAI) and myeloperoxidase activity (MPO). Observed amelioration of the disease in TNP-Ig patched mice was accompanied with decreased production of IFN-γ and IL-17A by splenocytes. Additionally, spleen cells isolated from mice EC immunized with TNP-Ig prior to colitis induction showed increased production of IL-10 suggesting that this cytokine might be involved in inhibiting inflammatory response in the colon. This work shows that EC immunization with protein antigen prior to TNBS-colitis induction ameliorates disease and observed suppression of inflammatory response in the colon might be mediated by IL-10.