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The cyclin-dependent kinase inhibitors are key regulators of cell cycle progression. Although implicated in carcinogenesis, they inhibit the proliferation of a variety of normal cell types, and their role in diverse human diseases is not fully understood. Here, we report that p27Kip1 plays a major role in cardiovascular disease through its effects on the proliferation of bone marrow-derived (BM-derived) immune cells that migrate into vascular lesions. Lesion formation after mechanical arterial injury was markedly increased in mice with homozygous deletion of p27Kip1, characterized by prominent vascular infiltration by immune and inflammatory cells. Vascular occlusion was substantially increased when BM-derived cells from p27−/− mice repopulated vascular lesions induced by mechanical injury in p27+/+ recipients, in contrast to p27+/+ BM donors. To determine the contribution of immune cells to vascular injury, transplantation was performed with BM derived from RAG−/− and RAG+/+ mice. RAG+/+ BM markedly exacerbated vascular proliferative lesions compared with what was found in RAG−/− donors. Taken together, these findings suggest that vascular repair and regeneration is regulated by the proliferation of BM-derived hematopoietic and nonhematopoietic cells through a p27Kip1-dependent mechanism and that immune cells largely mediate these effects.