A combination of selective COX-2 inhibitors and hydrogen peroxide increase the reactive oxygen species formation in osteosarcoma cells after X-ray irradiation. We investigated whether a combination of selective COX-2 inhibitors and hydrogen peroxide increases the effect of X-ray irradiation, with regard to reactive oxygen species (ROS) formation in an osteosarcoma cell line. COX-2 inhibitor did not induce ROS formation when combined with irradiation. A low dose concentration of COX-2 inhibitor in combination with hydrogen peroxide and irradiation did affect ROS formation in the intracellular compartment; however, this same combination of agents at high doses did not modulate the effect of irradiation. Therefore, low doses of COX-2 inhibitor and hydrogen peroxide together, in combination with irradiation, is a potentially useful alternative form of radiotherapy for apoptotic-resistant neoplasms such as osteosarcoma.