Angiotensin (Ang) II plays a critical role in cardiovascular remodeling. Krüppel-like factor (KLF) 5 is a novel indicated mediator in Ang II-induced cardiovascular damage. However, the potential link between KLF5 and Ang II has not been well investigated. In this study, we showed that in growth-arrested vascular smooth muscle cells (VSMCs), Ang II induced cell proliferation, KLF5 mRNA and protein expression in a dose- and time-dependent fashion, whereas KLF5 mRNA stability was not affected. The AT1 antagonist losartan significantly blocked Ang II-induced KLF5 expression. Furthermore, several intracellular signals elicited by Ang II were involved in KLF5 gene upregulation, including phosphate tyrosine kinase, mitogen-activated protein kinases and reactive oxygen species. These data, for the first time, revealed the involvements of some intracellular signals in the regulation of KLF5 expression in response to Ang II in VSMCs and showed the possible role of KLF5 in Ang II-induced cell proliferation in VSMCs.