We identified the G protein coupled relaxin receptor RXFP1 in glioblastoma (GB) and discovered C1q-tumor necrosis factor related protein 8 (CTRP8) as a novel ligand of RXFP1 in this common and most aggressive form of brain tumor. The known RXFP1 ligand relaxin isoform 2 (RLN2) is not expressed in the brain indicating that RXFP1 signaling in GB is activated by auto-/paracrine secretion of CTRP8. In GB, RXFP1 signaling included PI3K and PKC activation and resulted in the increased production and secretion of lysosomal protease cathepsin B, a known prognostic marker of GB. In the present study, we have investigated the potential role of RXFP1 in chemoresistance to the commonly used DNA alkylating drug temozolomide (TMZ) in human GB. Upon TMZ treatment, CTRP8/RLN2 mediated activation of RXFP1 was able to mitigate DNA damage in human primary GB cells and enhanced their survival. Activation of RXFP1 resulted in STAT3 pathway activation and the RXFP1- and STAT3-dependent up-regulation of proteins and their activity deemed important for TMZ-induced DNA damage repair. Furthermore, RXFP1 activation resulted in the up-regulation of key anti-apoptotic factors in human GB cells. Our results indicate a novel role for the CTRP8-RXFP1 ligand-receptor system in STAT3-dependent cell invasion, TMZ chemoresistance, and survival and identify RXFP1 as a new protective G protein coupled receptor in GB cells.