Significance Preservation and/or enhancement of Treg function is becoming a key component of modern immunotherapeutic strategies, but the direct influence of many immunosuppressive drugs on Tregs remains unknown. Calcineurin inhibitors (CNIs), which are widely used to treat inflammatory disorders, reduce the size of the Treg pool substantially, and this reduction might hinder their overall beneficial effects. Here we show that the decrease in Treg numbers is caused by increased cell death as a result of the limited availability of the IL-2 growth factor. Hence, the addition of IL-2 restores the survival and suppressive properties of Tregs exposed to CNIs and improves allograft survival. Our data provide a strong rationale for combining CNIs with IL-2 therapy to maximize effective immunosuppression and to promote tolerance acquisition.