Objective-MED1　(mediator　1)　interacts　with　transcription　factors　to　regulate　transcriptional　machinery.　The　role　of　MED1　in　macrophage　biology　and　the　relevant　disease　state　remains　to　be　investigated.　Approach　and　Results-To　study　the　molecular　mechanism　by　which　MED1　regulates　the　M1/M2　phenotype　switch　of　macrophage　and　the　effect　on　atherosclerosis,　we　generated　MED1/apolipoprotein　E　(ApoE)　double-deficient　(MED1　Delta　Mac/ApoE(-/-))　mice　and　found　that　atherosclerosis　was　greater　in　MED1(Delta　Mac)/ApoE(-/-)mice　than　in　MED1(fl/fl)/ApoE(-/-)littermates.　The　gene　expression　of　M1　markers　was　increased　and　that　of　M2　markers　decreased　in　both　aortic　wall　and　peritoneal　macrophages　from　MED1(Delta　Mac)/ApoE(-/-)mice,　whereas　MED1　overexpression　rectified　the　changes　in　M1/M2　expression.　Moreover,　LDLR　(low-density　lipoprotein　receptor)-deficient　mice　received　bone　marrow　from　MED1(Delta　Mac)　mice　showed　greater　atherosclerosis.　Mechanistically,　MED1　ablation　decreased　the　binding　of　PPAR　gamma　(peroxisome　proliferator-activated　receptor　gamma)　and　enrichment　of　H3K4me1　and　H3K27ac　to　upstream　region　of　M2　marker　genes.　Furthermore,　interleukin　4　induction　of　PPAR.　and　MED1　increased　the　binding　of　PPAR　gamma　or　MED1　to　the　PPAR　response　elements　of　M2　marker　genes.　Conclusions-Our　data　suggest　that　MED1　is　required　for　the　PPAR.-mediated　M2　phenotype　switch,　with　M2　marker　genes　induced　but　M1　marker　genes　suppressed.　MED1　in　macrophages　has　an　antiatherosclerotic　role　via　PPAR　gamma-regulated　transactivation.