Purpose: In the ileum of W/W^v mutant mice (W/W^v), the absence of interstitial cells of Cajal (ICC) in the myenteric region (ICC-MY), and cross-talk between ICC in the deep muscular region (ICC-DMP) and enteric nitrergic motor nerves leads to irregular spontaneous electrical and contractile activity. The aim of the present study was to reveal changes in this irregular spontaneous electrical and contractile activity in the ileum of dextran sodium sulfate (DSS: m.w. 40,000)-induced colitis model W/W^v mice. Methods: Electrical and contractile activity was recorded with a suction electrode and with both an isometric force transducer and a pressure transducer in the ileum of W/W^v mice either with DSS-induced colitis (DSS (+)) in the distal colon or without in controls (DSS (–)). Neuronal NO synthase (nNOS) and inducible NO synthase (iNOS) immunoreactivity in the ileum was compared between the following groups of mice: W/W^v DSS (+), W/W^v DSS (–), wild type (WT) with (DSS (+)) and WT without DSS-induced colitis (DSS (–)). Results: DSS induced colitis in the distal colon of W/W^v mice is reduced compared with that in WT mice, despite the reduction in the number of mast cells in the W/W^v mutants. Irregular contractions in the ileum without colitis were strongly suppressed in W/W^v DSS (+) mice. The mean interval of irregular contractions in W/W^v DSS (+) mice was 5-fold larger than that in W/W^v DSS (–) mice. N-nitro-L-arginine methyl ester (L-NAME) facilitated the frequency of irregular contractions in the ileum without colitis in W/W^v DSS (+) mice. L-NAME decreased the mean interval of contractions to one-fourth in the ileum of W/W^v DSS (+) mice, where strong iNOS immunoreactivity in nitrergic motor nerves was found with unchanged nNOS immunoreactivity. Conclusions: The stronger suppression of irregular contractions of the ileum in DSS-induced colitis model W/W^v mice was elicited and mediated by cross-talk between ICC-DMP and enteric nitrergic motor nerves expressing iNOS/NO, even though the ileum was not demonstrating colitis.