This study was designed to test the hypothesis of a major gene influence on the variation in bone mineral density (BMD). BMD and bone mineral content at the lumbar spine and femoral neck were measured in 330 men and 413 women, aged 18-90 yr, from 107 nuclear and complex families (including 5 large pedigrees with 194 individuals who were identified through an index case with moderately high BMD at the femoral neck (z-score, >or=1.28)). After adjusting for age and body weight, familial factors accounted for up to 72% of the total variation in BMD. In complex segregation analysis, for all variables examined the best-fitting most parsimonious model consistently suggested the Mendelian transmission of a major gene locus with significant residual correlations among siblings. This genetic model suggested that the proportion of a total variance (adjusted for significant covariates) attributable to a putative major gene effect ranged between 0.30 +/- 0.09 for femoral neck BMD and 0.53 +/- 0.07 for the principal component obtained on BMD and corresponding bone mineral content measures. These findings clearly support the hypothesis that a large component of the variance in BMD is under genetic control, with strong evidence for a major gene locus influencing BMD transmission.