Both CTLA‐4‐deficient and FoxP3‐deficient mice exhibit a short life span due to massive lymphoproliferation (LP) and a systemic autoimmune‐like syndrome. Although it has been postulated that both diseases result from regulatory T cell (T_reg) defects, there have been no direct complementation studies to elucidate their relationship in homeostatic lymphocyte proliferation during the neonatal period. In this study, reconstitution of sublethally irradiated RAG KO mice with either CTLA‐4‐deficient or FoxP3‐deficient bone marrow (BM) resulted in LP disease similar to that observed in CTLA‐4 KO or Scurfy mice, respectively. Although co‐injection of BM from wild‐type mice inhibited the activation of CTLA‐4‐deficient or FoxP3‐deficient T cells and ameliorated LP disease through extrinsic regulatory mechanisms by T_reg cells, mice that had received the BM mixture of Scurfy and CTLA‐4 KO BM eventually died of incomplete protection. These results suggest common attributes of both diseases, but expression of both CTLA‐4 and FoxP3 on the same cell subset is essential to fully prevent LP disease.