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 p27^Kip1 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 p27^Kip1, 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 p27^Kip1-dependent mechanism and that immune cells largely mediate these effects.