Vitamin D is known to be closely associated with periodontitis; however,its exact mechanisms remain to be clarified. The present study aimed to investigate the influence of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3 on Porphyromonas gingivalis (Pg)-stimulated cytokine production and the involved signaling pathways in macrophages. The main observation was that 1,25(OH)2D3 inhibited Pg-induced interleukin (IL)-6 cytokine expression but up-regulated the expression of antiinflammatory cytokine IL-10. Further analyses showed that 1,25(OH)2D3 decreased p38 mitogen-activated protein kinase (MAPK) and extracellular signal regulated kinase (ERK)1/2 phosphorylation. Inhibited phosphorylation of p38 MAPK and ERK1/2 was associated with decreased level of IL-6 expression,but was not related to increased level of IL-10 expression in macrophages stimulated with Pg. These results suggest that 1,25(OH)2D3 might exert its anti-inflammatory effects on Pg-stimulated macrophages partly through its inhibitory effect on the p38 MAPK and ERK1/2 signaling pathway.