The effects of polymorphisms in ERCC5, ERCC6, XPC, CCNH and MMS19L on osteosarcoma response tochemotherapy and the survival of the affected patients were assessed. Genotyping of ERCC5, ERCC6, XPC,CCNH and MMS19L was performed by PCR-RFLP assay. The median PFS was 12.8 months, and the medianOS was 18.6 months. Individuals carrying homozygous genotypes of ERCC5 rs17655 and ERCC5 rs1047768were more like to have good response to treatment, while those carrying homozygous genotypes of MMS19Lrs29001322 showed poor response. Osteosarcoma patients carrying TT genotype of ERCC5 rs1047768 showeda significantly longer PFS (16.8 months) and OS (21.4 months) than CC genotype, with HRs(95% CI) of 0.31(0.10-0.93) and 0.32 (0.06-0.97), respectively. Conversely, those with the TT genotype of MMS19L rs29001322demonstrated shorter PFS and OS, the HRs (95% CI) being 2.23 (1.08-4.15) and 4.62 (1.45-16.08), respectively.Our findings showed polymorphisms in ERCC5 rs1047768 and MMS19L rs29001322 to be associated withclinical outcome of osteosarcoma patients undergoing chemotherapy.