Huntington's disease (HD) is a polyglutamine-expansion disease associated to degeneration of striatal and cortical neurons. Previously, we showed that oxidative stress occurs in HD knock-in striatal cells, but little is known regarding cell antioxidant response against exogenous stimuli. Therefore, in the present study we analysed cellular antioxidant profile following hydrogen peroxide (H2O2) and staurosporine (STS) exposure, and tested the protective effect of cystamine and creatine in striatal cells expressing mutant huntingtin with 111 glutamines (STHdh(Q111/Q111); mutant cells) versus wild-type cells (STHdh(Q7/Q7)). Mutant cells displayed increased mitochondrial reactive oxygen species (ROS) and decreased NADPH oxidase and xanthine oxidase (XO) activities, reflecting lower superoxide cytosolic generation, along with increased superoxide dismutases (SODs) and components of glutathione redox cycle. Exposure to H(2)O(2) and STS enhanced ROS in mutant cells and largely increased XO activity; STS further boosted the generation of mitochondrial ROS and caspase-3 activity. Both stimuli slightly increased SOD1 activity, without affecting SOD2 activity, and decreased glutathione reductase (GRed) with a consequent rise in GSSG in mutant cells, whereas H(2)O(2) only increased glutathione peroxidase (GPx) activity. Additionally, creatine and cystamine increased mutant cells viability and prevented ROS formation in HD cells subjected to H(2)O(2) and STS. These results indicate that elevation of the antioxidant systems accompanies mitochondrial-driven ROS generation in mutant striatal cells and that exposure to noxious stimuli induces a higher susceptibility to oxidative stress by increasing XO activity and lowering the antioxidant response. Furthermore, creatine and cystamine are efficient in preventing H(2)O(2-) and STS-evoked ROS formation in HD striatal cells.