Family and twin studies demonstrate a strong genetic component to osteoporosis, suggesting that a positive family history for this disease may be an important clinical risk factor. We have therefore explored the extent to which a history of wrist fracture in a female first-degree relative was associated with an increased risk of prevalent fracture at both appendicular and vertebral sites in a cross-sectional study design. One thousand and three Caucasian women (age range 45-64 years) were studied from a UK population cohort. Bone mineral density (BMD) was measured at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry. Appendicular fractures (wrist and hip) were recorded by questionnaire and validated from radiographs and hospital records. Vertebral fractures were assessed using radiologic survey of the thoracolumbar spine and semi-automated morphometric analysis. A positive family history of osteoporotic fracture (hip and/or wrist) in either a mother and/or sister was reported in 138 of the 1003 women. When compared with those with a negative family history of fracture, BMD was significantly reduced in those with a positive history at both the spine (p = 0.02) and the hip (p = 0.02). In total, there were 63 validated fragility fractures found in the 1003 women (16 wrist, 6 hip and 41 vertebral). Family history of osteoporotic fracture was associated with an increased total risk for osteoporotic fracture, with an odds ratio (95% confidence interval) of 2.02 (1.02, 3.78). Site-specific analysis showed that a positive family history of wrist fracture was associated with a considerably elevated risk of wrist fracture, with an odds ratio of 4.24 (1.44, 12.67). These increases in risk remained after adjustment for BMD, suggesting that other genetic factors account for the familial risk of osteoporosis and fracture.