Gaining an understanding of factors contributing to bone quality is key to the development of effective preventative treatments for osteoporosis and reduction in osteoporotic fractures. Oestrogen is a strong regulator of bone remodelling which maintains skeletal structural integrity. The growth regulation by oestrogen in breast cancer 1 (GREB1) gene, with an as yet undefined function, is an early response gene in the oestrogen-regulated pathway. Suggestive evidence of linkage with bone mineral density (BMD) variation has been reported with D2S168, located telomeric of GREB1. The aim of this study was to determine if genetic variation within GREB1 was associated with BMD variation at two sites with high fracture rates-the lumbar spine (LS) and the femoral neck (FN). Informative GREB1 single-nucleotide polymorphisms (SNPs) (n = 12) were selected for genotyping and tested for association in a family-based dataset (n = 508 individuals from 229 families). Significantly associated SNPs were tested further in a postmenopausal dataset from the same geographic region (n = 477 individuals). One intronic SNP, rs5020877, was significantly associated with LS and FN BMD in the family-based dataset (P ≤ 0.005). The association was not observed in the postmenopausal dataset (P > 0.017); however, rs10929757 was significantly associated with FN BMD (P = 0.006). Markers, rs5020877 and rs10929757, were constituent SNPs in one GREB1 linkage disequilibrium block, although not historically correlated (r 2 = 0.07). Our findings suggest that GREB1 is a novel gene target for osteoporosis genetics and needs to be investigated further.