Aim To investigate the signal transduction of neutrophils adhesion to human umbilical vein endothelial cells (hUVEC, ECV304) induced by hypoxia/reoxygenation. Methods The adhesion model was reproduced by hypoxia/ reoxygenation. The adhesion rate of neutrophils to ECV304 was determined by color matching. The expression of endothelial cell adhesion molecules of E-selectin and intercellular adhesion molecule-1 (ICAM-1) was measured with flow cytometry. The expression of cyclophilin A and the activation of extracellular signal-regulated kinase (ERK1/2) and p70 ribosomal S6 kinase (p70 S6K) were compared among experimental groups by western blot. Results After stimulation with 1 h hypoxia/4 h reoxygenation, ECV304 showed an enhanced neutrophil adhensivity in the association with an increased surface expression of E-selectin and ICAM-1. Furthermore, the expression of cyclophilin A increased significantly following 1 h hypoxia/4 h reoxygenation, which was accompanied with an increased activation of ERK1/2 and p70 S6K. Treatment with cyclophilin A inhibitor cyclosporin A and cyclophilin A antisense oligodeoxynucleotides significantly inhibited the activation of ERK1/2 and p70 S6K and decreased the adhesion of neutrophils to ECV304. p70 S6K antagonist rapamycin also significantly decreased the adhesion of neutrophils to ECV304. The specific ERK1/2 inhibitor PD98059 showed inhibition to neutrophils adhesion to hypoxia/reoxygenation-stimulated ECV304. Conclusions Cyclophilin A-ERK1/2-p70 S6K pathway is involved in the adhesion of neutrophils to ECV304 induced by hypoxia/reoxygenation.