The NADPH oxidases (Noxes) are a family of ROS (reactive oxygen species)-generating enzymes which play a critical role in the development of cardiac remodeling associated with heart failure. The Noxes of their catalytic isoforms include multiple homologues in cardiovascular cells with wide range tissue distribution. It is still unclear which Noxes represent the major enzymatic source of ROS in the heart and play a predominant role in cardiac hypertrophy. In this study we investigated the differential expression changes of NAD(P)H oxidase P47phox isoform and Nox homologues in left ventricle and the effects of atorvastatin on cardiac remodeling in two-kidney two-clip(2K2C) hypertensive rats. The mRNA and protein expression of Nox2, Nox4 and P47phox showed a sustained increase at 4, 8, 12 weeks after surgery in 2K2C rats. Administration of atorvastatin attenuated cardiac dysfunction, hypertrophy and fibrosis of 2K2C rats. However, atorvastatin treatment had no effects on BP regulation. Further studies revealed that atorvastatin inhibited the increased expression of Nox2, Nox4, P47phox as well as 02"- production in 2K2C hypertensive rats. These findings indicate that Nox2, Nox4 and P47phox play a crucial role in the development of cardiac remodeling in the 2K2C hypertensive rats. Atorvastatin, independent of BP control, exerts anti-remodeling effects partially by inhibition of NAD(P)H oxidase-mediated cardiac oxidative stress.