CD44, a glycoprotein, has been reported to have relationship with resistance to radiation in prostate cancer (Cap) cells. However, its molecular mechanism remains unknown. In this study, we demonstrated that inhibited CD44 enhanced the radiosentivity in Cap cells. It has been hypothesized that CD44 combine with ERBB2 and activate downstream phosphated protein to mediate DNA damage repair. Therefore, we conducted a detailed analysis of effects of radiation by clonogenic assay and immunofluorescence stain for p-H2AX foci. The downstream of CD44/ERBB2 and DNA damage repair proteins was detected by western blot. The results reveal that CD44 interacted with ERBB2, the downstream of CD44/ERBB2 was p-p38 when Cap cells were irradiated. Among the pathways, homologous recombination (HR) related proteins Mre11 and Rad50 were involved in CD44/ERBB2/p-p38 mediated radioresistance in Cap. In conclusion, CD44 could stabilize ERBB2 and co-activate p-p38 expression then promote the DNA damage repair by HR pathway, which finally contribute to the radioresistance of CaP.