Aim To explore the effect of momordicin on nuclear translocation of inflammatory factor nuclear factor-kappa B (NF-κB) in ApoE^-/- mice and further analyze the molecular mechanisms related to momordicin anti-inflammatory. Methods 40 male ApoE^-/- mice, 6 weeks old, were randomly divided into four groups: normal food group, high fat high cholesterol group, high fat high cholesterol and momordicin group, normal food and momordicin group. After feeding 12 weeks, all mice were removed eyeball in order to obtain blood preparation. Level of inflammatory factors (IL-1β, TNF-α, IL-6, IFN-γ) and anti-inflammatory factors (IL-10) were measured by ELISA, IκB expression of aorta was analyzed by immunohistochemistry. Gene and protein expression was analyzed by semi-quantitative RT-PCR and Western blot, respectively. Results After fed with high fat high cholesterol about 12 weeks, inflammatory factors (IL-1β, TNF-α, IL-6, IFN-γ) level increased compared with normal food group(P<0.01, n5), but the level of IL-10 can not be up-regulated. After momordicin treating, inflammatory factors level decreased, yet IL-10 can not increase. Not only momordicin inhibited p65 mRNA transcription compared with high fat high cholesterol group, but also the nuclear level of NF-κB of momordicin treat group were obviously lower than high fat high cholesterol group in artery wall, nuclear translo cation of NF-κB was inhibited by momordicin treating. IκB in high fat high cholesterol group was remarkably reduced compared with normal food group (0.19±0.05 vs 0.74±0.15, P<0.05, n5), but this reduction can be obviously inhibited by momordicin intervention(0.19±0.05 vs 0.36±0.07, P<0.01,n5). Conclusions The role of momordicin anti-inflammatory factors generation is related to inhibiting degradation of IκB, which inhibits nuclear translocation of NF-κB.