High reactive oxygen species (ROS), Ha-Ras, and active ERK1/2 in fibroblasts play an essential role in the pathogenesis of systemic sclerosis (SSc). The present study was carried out to evaluate the effects of the ethanol extract from fruits of Capparis Spinosa L. (ECS) on oxidative stress and ROS-ERK1/2-Ha-Ras signal loop in SSc dermal fibroblasts in vitro. Cultured dermal fibroblasts from three SSc patients and three normal controls were treated with ECS by different concentration (10, 50, 100 microg/ml). ECS significantly reduced the production of O2(-), H2O2, and ROS in SSc fibroblasts in a dose-dependent manner. ECS effectively minimized the loss of cell viability and apoptosis induced by H2O2 in normal and SSc fibroblasts. Furthermore, the protective effect of ECS on SSc fibroblasts was more significant than on normal ones. ECS decreased the expression of P-ERK1/2 and Ha-Ras in a dose-dependent manner. In conclusion, ECS exhibits a notable activity in protecting against oxidative stress and interrupting of ROS-ERK1/2-Ha-Ras signal loop in SSc, suggesting its potential protective effects against skin sclerosis.