Background: The vagus nerve inhibits the response to systemic administration of endotoxin and we have recently extended this observation to show that the vagus attenuates acute experimental colitis in mice. The purpose of the present study is to determine whether there is a tonic counter-inflammatory influence of the vagus on colitis maintained over several weeks. Methods: We assessed disease activity index, macroscopic and histological damage, myeloperoxidase (MPO) activity, Th1 and Th2 cytokines profile, in chronic colitis induced by administration of dextran sodium sulphate in drinking water for 3 cycles during 5 days with 11 days of rest between each cycle (DSS 3,2,2%), in healthy and vagotomized C57BL/6 and in mice deficient in macrophage-colony stimulating factor (M-CSF). A pyloroplasty was performed in vagotomized mice. Results: Vagotomy accelerated the onset and the severity of inflammation during the 1^st and 2^nd, but not the 3^rd cycle. While macroscopic scores were not significantly changed, histological scores as well as MPO activity, colonic tissue levels of interleukin(IL)-1beta, tumor necrosis factor-alpha, interferon-gamma, IL-18, but not IL-4, were significantly increased in vagotomized mice compared to sham-operated-mice that received DSS. In control mice (without colitis) vagotomy per se did not affect any inflammatory marker. Vagotomy had no effect on the colitis in M-CSF-derived macrophage deficient mice. Conclusions: These results indicate that the vagus protects against acute relapses on a background of chronic inflammation. Identification of the molecular mechanisms underlying the protective role of parasympathetic nerves opens new therapeutic avenue for the treatment of acute relapses of chronic IBD.