Peroxisome proliferator-activated receptor gamma (PPARG) is a ligand-activated transcription factor regulating metabolic and vascular function. We previously reported that mice (S-DN) expressing dominant-negative PPARG in smooth muscle cells (SMC) are hypertensive, exhibit impaired vascular relaxation, and display reduced expression of a novel PPARG target gene, RhoBTB1. We hypothesized that RhoBTB1 may play a protective role in vascular function that is disrupted in S-DN mice and in other models of hypertension. We then generated double transgenic mice (termed S-RhoBTB1) with tamoxifen-inducible, Cre-dependent expression of RhoBTB1 in SMC. S-RhoBTB1 mice were crossed with S-DN to produce mice (S-DN/S-RhoBTB1) in which tamoxifen-treatment restored RhoBTB1 expression in aorta to normal. Increased blood pressure (BP) and impaired vasodilation in S-DN were reversed by restoration of RhoBTB1 in SMC. To test if RhoBTB1 can prevent angiotensin (Ang) II-induced hypertension, Ang II (490 ng/min/kg) was infused in tamoxifen-treated S-RhoBTB1 for two weeks. Ang II-induced increased BP and impaired vasodilation were blunted in S-RhoBTB1. We conclude that a novel PPARG target gene, RhoBTB1, functions in SMC to facilitate vasodilation and mediates a protective anti-hypertensive effect.