Cold inducible RNA binding protein (CIRP), also named A18 hnRNP or CIRBP, is a cold-shock RNA-binding protein which can be induced upon various cellular stresses. Its expression level is induced in various cancer tissues relative to adjacent normal tissues; this is believed to play a critical role in cancer development and progression. In this study, we investigated the role of CIRP in cells exposed to ionizing radiation. Our data show that CIRP reduction causes cell colony formation and cell viability reduction after irradiation. In addition, CIRP knockdown cells demonstrated a higher DNA damage rate but less cell cycle arrest after irradiation. As a result, the induced DNA damage with less DNA repair processes led to an increased cell apoptosis rate in CIRP knockdown cells postirradiation. These findings suggest that CIRP is a critical protein in irradiated cells and can be used as a potential target for sensitizing cancer cells to radiation therapy.