All current smooth muscle cell (SMC) Cre mice similarly recombine floxed alleles in vascular and visceral SMCs. Here we present an Itga8-CreER^T2 knock-in mouse and compare its activity with a Myh11-CreER^T2 mouse. Both Cre drivers demonstrate equivalent recombination in vascular SMCs. However, Myh11-CreER^T2 mice, but not Itga8-CreER^T2 mice, display high activity in visceral SMC-containing tissues such as intestine, show early tamoxifen-independent activity and produce high levels of CreER^T2 protein. Whereas Myh11-CreER^T2-mediated knockout of serum response factor (Srf) causes a lethal intestinal phenotype precluding analysis of the vasculature, loss of Srf with Itga8-CreER^T2 (Srf^Itga8) yields viable mice with no evidence of intestinal pathology. Male and female Srf^Itga8 mice exhibit vascular contractile incompetence, and angiotensin II causes elevated blood pressure in wild-type, but not Srf^Itga8, male mice. These findings establish the Itga8-CreER^T2 mouse as an alternative to existing SMC Cre mice for unfettered phenotyping of vascular SMCs after selective gene loss.