Wound healing is a complex process, which is classically divided into inflammation, proliferation, and remodeling phases. Macrophages play a key role in wound healing, however, whether E2F1 mediates the M1/M2 polarization during the wound healing process is not known. Skin wounds were surgically induced in E2F1(-/-) mice and their WT littermates. At day 2 and day 7 post-surgery, the wounded skin tissues including 2 to 3 mm normal skin were obtained. The wounded skin tissues were used for the analyses of immunofluorescence staining (CD68, iNOS, CD206), western blotting (CD68, iNOS, CD206, PPAR-gamma) and Co-immunoprecipitation (E2F1-PPAR-gamma interactions). E2F1(-/-) mice exhibited faster wound healing process. At day 2, the M2 macrophages were remarkably increased in the E2F1(-/-) mice. Surprisingly, in the border zone of the wound, E2F1(-/-) mice had also more M2 macrophages and fewer M1 macrophages at day 7 post-surgery, suggesting a certain degree of polarization amongst the M1 and M2 phenotypes. Co-IP revealed that E2F1 indeed interacted with PPAR-gamma, meanwhile western blotting and RT-PCR showed higher expression of PPAR-gamma in the E2F1(-/-) mice as compared to that in the WT mice. Therefore, the findings suggest that wound healing process could be accelerated with enhanced M2 polarization through increased PPAR-gamma expression in E2F1 knockout mice.