Corticosteroid therapy (CST) is associated with reduced intestinal calcium absorption, bone loss and increased fracture risk. As polymorphisms of the vitamin D receptor (VDR) gene may be associated with bone mineral density (BMD) and intestinal calcium absorption, we asked whether patients with a given VDR genotype receiving CST may be at increased or decreased risk for corticosteroid-related bone loss and osteoporosis. We measured areal BMD (g/cm2) by dual-energy X-ray absorptiometry in 193 women (50 premenopausal, 143 postmenopausal) and 70 men with rheumatoid arthritis (n = 44), obstructive airway diseases (n = 128) and other corticosteroid-treated diseases (n = 91). All patients received a cumulative dose greater than 1.8 g per year or a minimum of 5 mg daily of prednisolone or equivalent for at least 1 year. VDR alleles were typed by polymerase chain reaction assay based on the polymorphic BsmI and TaqI restriction sites. BMD in patients was expressed as a Z-score (mean +/- SEM) derived from age- and gender-matched controls. BMD was reduced in patients at the lumbar spine (bb, -0.52 +/- 0.12; Bb, -0.47 +/- 0.11; BB, -0.65 +/- 0.18 SD; p < 0.01), femoral neck (bb, -0.46 +/- 0.10; Bb, -0.34 +/- 0.10; BB, -0.54 +/- 0.14 SD; p < 0.01), Ward's triangle (bb, -0.44 +/- 0.10; Bb, -0.31 +/- 0.10; BB, -0.45 +/- 0.13 SD; p < 0.01), and trochanter (bb, -0.50 +/- 0.10; Bb, -0.30 +/- 0.10; BB, -0.44 +/- 0.14 SD; p < 0.01). However, there was no significant difference in the deficit in BMD in any of the genotypes, either before or after adjusting for age, sex, body mass index, disease type, age at onset of disease, disease duration, cumulative steroid dosage, smoking status and dietary calcium intake. Similarly, there were no detectable differences between the BsmI genotypes and the rate of bone loss in 79 patients with repeated BMD measurements at an interval of 4-48 months. The data suggest that the VDR genotypes may not be a means of identifying patients at greater risk of corticosteroid-related bone loss.