The expression of the inducible form of nitric oxide synthase (NOS2) is reduced in cystic fibrosis (CF) epithelium despite the presence of aggressive inflammation. A potential mechanism for reduced NOS2 expression in CF is diminished signal transducer and activator of transcription-1 (STAT1) activity, possibly due to an increase in expression of protein inhibitor of activated STAT1 (PIAS1). Previous evidence also suggests that NOS2 expression can be negatively regulated by increased activation of the GTPase RhoA, leading to the hypothesis that CF-related increases in PIAS1 expression and altered STAT1 signaling may be mediated by Rho GTPase function. Consistent with this hypothesis, data demonstrate increased expression of RhoA in two models of CF epithelium with a proportional increase in the active GTP-bound RhoA. Mouse embryonic fibroblasts null for p190B Rho GTPase-activating protein exhibit increased RhoA protein content and activation, similar to what is observed in CF models, and also exhibit CF-like alterations in STAT1 regulation, including decreased STAT1 activation, increased PIAS1 protein expression, and reduced NOS2 induction, implicating RhoA-mediated signaling in CF-related STAT1 alterations. Inhibition of the Rho GTPase pathway at the level of isoprenoid/cholesterol synthesis with mevastatin reduces PIAS1 expression, increases STAT1 activation, and restores NOS2 expression in models of CF epithelium, suggesting that pharmacological inhibition of the isoprenoid synthesis/Rho GTPase pathway may represent a potential avenue for therapeutic intervention for CF.