Genetic factors play an important role in the pathogenesis of osteoporosis and several candidate gene polymorphisms have been implicated in the regulation of this process. One of the most widely studied is the Sp1 binding site polymorphism in the COL1A1 gene. This polymorphism has been associated with BMD and osteoporotic fracture in several studies, but the data from different studies have been conflicting. Here we have attempted to clarify the association between COL1A1 Sp1 alleles, BMD, and osteoporotic fracture by conducting a meta-analysis of 26 published studies including 7849 participants. Under a fixed effects model, BMD values at the lumbar spine (6800 subjects) were significantly lower in the "Ss" genotype group when compared with "SS" homozygotes (standardized mean difference = 0.131 [95% CI, 0.06,0.16], P = 0.00005) but the difference was not significant for the "ss" comparison (0.09 [-0.03,0.21], P = 0.13). At the femoral neck (6750 subjects) BMD values were lower in the "Ss" genotype (0.14 [0.08,0.19], P < 0.00001) and lower still in the "ss" genotype group (0.19 [0.07,0.31], P = 0.001). Similar results were found when the data were analyzed under a random effects model. Analysis of fracture data (6961 subjects) showed an increased odds ratio for any fracture in "Ss" subjects (1.26 [95% CI 1.09,1.46], P = 0.002) and an even greater increase in "ss" subjects (1.78 [1.30,2.43], P = 0.0003). Subgroup analysis showed that increased risk was largely attributable to vertebral fracture where the odds ratio was 1.37 [1.15,1.64] for "Ss" (P = 0.0004) and 2.48 [1.69,3.65] for "ss" (P < 0.00001). The risk of nonvertebral fracture was not increased in relation to the COL1A1 genotype, although power to detect an effect was limited by the fact that fewer studies had analyzed nonvertebral fracture. We conclude that the COL1A1 Sp1 alleles are associated with a modest reduction in BMD and a significant increase in risk of osteoporotic fracture, particularly vertebral fracture.