OBJECTIVE Negative pressure wound therapy displayed significant clinical benefits in the healing of diabetic foot wounds. In the present study, we investigated the mechanism of regulation of MAPK-JNK (Mitogen-activated protein kinase- c-Jun N-terminal kinase) signaling pathway by negative pressure wound therapy on these wounds. METHODS Twenty-six type 2 diabetes patients with foot ulceration were randomly assigned to the two groups, thirteen treated with negative pressure wound therapy and the others treated with traditional debridement therapy. Skin samples were harvested and histologically and immunohistochemical analyzed in both groups. Immunofluorescence stain, Enzyme-linked immunosorbent assay and Western blotting were performed for inducible nitric oxide synthase, inter leukin-6, tumor necrosis factor-α, P-c-Jun N-terminal kinase and c-Jun N-terminal kinase. Real time-polymerase chain reaction was performed to evaluate expression of c-Jun N-terminal kinase, extracellular signal regulated kinase1/2 and p38. RESULTS Negative pressure wound therapy could effectively alleviate inflammatory reaction and reduce inter leukin-6 and inducible nitric oxide synthase production after 7 days treatment. The level of tumor necrosis factor-α, inter leukin-6 and P-c-Jun N-terminal kinase were significantly decreased. However, there was no statistical difference in messenger ribonucleic acid expression of p38, extracellular signal regulated kinase1 and 2. CONCLUSIONS Negative pressure wound therapy possibly suppress the wound inflammation by inhibiting inter leukin-6, tumor necrosis factor-α and inducible nitric oxide synthase in diabetic foot patients. This effect is maybe mediated at least in part by suppression of Mitogen-activated protein kinase- c-Jun N-terminal kinase signaling pathway.