The immunosuppressive calcineurin inhibitors cyclosporine A and tacrolimus alter T cell subsets and can cause hypertension, vascular dysfunction, and renal toxicity. We and others have reported that cyclosporine A and tacrolimus decrease anti-inflammatory regulatory T cells and increase pro-inflammatory interleukin-17-producing T cells, therefore we hypothesized that inhibition of these effects using non-cellular therapies would prevent the hypertension, endothelial dysfunction, and renal glomerular injury induced by calcineurin inhibitor therapy. Daily treatment of mice with cyclosporine A or tacrolimus for 1 week significantly decreased CD4+/FoxP3+ regulatory T cells in the spleen and lymph nodes, as well as induced hypertension, vascular injury and dysfunction, and glomerular mesangial expansion in mice. Daily co-treatment with all-trans retinoic acid, reported to increase regulatory T cells and decrease interleukin-17-producing T cells, prevented all of the detrimental effects of cyclosporine A and tacrolimus. All-trans retinoic acid also increased regulatory T cells and prevented the hypertension, endothelial dysfunction, and glomerular injury in genetically modified mice that phenocopy calcineurin inhibitor-treated mice (FKBP12-Tie2 KO). Treatment with an interleukin-17 neutralizing antibody also increased regulatory T cell levels and prevented the hypertension, endothelial dysfunction, and glomerular injury in cyclosporine A-treated and tacrolimus-treated mice as well as FKBP12-Tie2 KO mice, while an isotype control had no effect. Augmenting regulatory T cells and/or inhibiting interleukin-17 signaling using non-cellular therapies prevents the cardiovascular and renal toxicity of calcineurin inhibitors in mice.