Aim To investigate the effect of OX40-OX40L interaction on the expression of nuclear factor of activated T cells c1 (NFATc1) and formation of the atherosclerotic plaques. Methods Atherosclerotic plaque model was randomly divided into the following groups:control group (n=11),OX40 activated group (n=11) and OX40 activated+PLKO.1-shNFATc1 group (n=11). Atherosclerotic plaque model was produced by perivascular carotid collar placement in ApoE－/－ mice. Masson staining was used to detect the composition of the plaque. Immunohistochemistry was used to observe the distribution of NFATc1 and CD68 in plaques. Mouse brain endothelial cells were divided into three groups:control group, OX40 activated group and OX40 inhibited group. The mRNA and protein level of NFATc1 was detected by real-time quantitative PCR (qRT-PCR) and Western blot respectively. Results In vitro, the expression level of NFATc1 was significantly increased in OX40 activated group, and were decreased in OX40 inhibited group(P<0.05). In vivo, the expression level of NFATc1 was significantly increased in OX40 activated group, and were decreased after the gene of NFATc1 being silenced(P<0.05). Masson staining revealed that the area of the plaque and fibrin proliferation was higher than the control group, while were decreased in OX40 activated+PLKO.1-shNFATc1 group. In vivo,compared with the control group, the distribution of NFATc1 and CD68 in the plaque were increased after the addition of agonist-OX40, which can be inhibited by silencing NFATc1. Conclusion OX40-OX40L interaction may regulate the expression of NFATc1 and promote the formation of the atherosclerotic plaque.