CTLA-4–deficient animals develop a fatal lymphoproliferative disorder. The cellular mechanism(s) responsible for this phenotype have not been determined. Here, we show that there is a preferential expansion of CD4⁺ T cells in CTLA-4^−/− mice, which results in a skewing of the CD4/CD8 T cell ratio. In vivo antibody depletion of CD8⁺ T cells from birth does not alter the onset or the severity of the CD28-dependent lymphoproliferative disorder. In contrast, CD4⁺ T cell depletion completely prevents all features characteristic of the lymphoproliferation observed in CTLA-4–deficient mice. These results demonstrate that CD4⁺ T cells initiate the phenotype in the CTLA-4^−/− mice. Further, these results suggest that the role of CTLA-4 in peripheral CD4⁺ versus CD8⁺ T cell homeostasis is distinct.