Curcumin (diferulolylmethane) demonstrates profound anti-inflammatory effects in intestinal epithelial cells (IEC) and in immune cells in vitro and exhibits a protective role in rodent models of chemically induced colitis, with its presumed primary mechanism of action via inhibition of NF-κB. Although it has been demonstrated effective in reducing relapse rate in ulcerative colitis patients, curcumin's effectiveness in Crohn's disease (CD) or in Th-1/Th-17 mediated immune models of CD has not been evaluated. Therefore, we investigated the effects of dietary curcumin (0.1–1%) on the development of colitis, immune activation, and in vivo NF-κB activity in germ-free IL-10−/−or IL-10−/−;NF-κBEGFPmice colonized with specific pathogen-free microflora. Proximal and distal colon morphology showed a mild protective effect of curcumin only at 0.1%. Colonic IFN-γ and IL-12/23p40 mRNA expression followed similar pattern (∼50% inhibition at 0.1%). Secretion of IL-12/23p40 and IFN-γ by colonic explants and mesenteric lymph node cells was elevated in IL-10−/−mice and was not decreased by dietary curcumin. Surprisingly, activation of NF-κB in IL-10−/−mice (phospho-NF-κBp65) or in IL-10−/−;NF-κBEGFPmice (whole organ or confocal imaging) was not noticeably inhibited by curcumin. Furthermore, we demonstrate that IL-10 and curcumin act synergistically to downregulate NF-κB activity in IEC and IL-12/23p40 production by splenocytes and dendritic cells. In conclusion, curcumin demonstrates limited effectiveness on Th-1 mediated colitis in IL-10−/−mice, with moderately improved colonic morphology, but with no significant effect on pathogenic T cell responses and in situ NF-κB activity. In vitro studies suggest that the protective effects of curcumin are IL-10 dependent.