Vertebral fractures are the most common osteoporotic fracture and are associated with significant pain and disability. Prior vertebral fracture and low bone mineral density (BMD) are strong predictors of new vertebral fracture. Using data from 6082 women, ages 55-80 years, in the Fracture Intervention Trial (a randomized, placebo-controlled trial of the antiresorptive agent, alendronate), we explored the association of the number of prior vertebral fractures with the risk of new fractures and whether this association is influenced by the spinal location of fractures. The risk of future vertebral fractures increased with the number of prevalent fractures, independently of age and BMD; in the placebo group, more than half of the women with five or more fractures at baseline developed new vertebral fractures, compared to only 3.8% of women without prior vertebral fractures. The magnitude of association with an increased risk of future vertebral fractures was equal for prevalent fractures located in either the "lower" (T12-L4) (relative risk [RR] = 2.9; 95% CI = 1.9, 3.6) or "upper" (T4-10) spine (RR = 2.6; 95% CI = 1.9, 3.6). We found no evidence that the effectiveness of alendronate in reducing the risk of future vertebral fracture was attenuated in women with up to five or more prevalent fractures, or that it varied by the location of prevalent fractures. However, prevalent vertebral fractures in any location were more strongly associated with risk of new fractures in the upper (RR = 5.2; 95% CI = 3.2, 8.3) than in the lower spine (2.3; 1.6, 3.3). In addition, each 1 SD decrease in spinal BMD was associated with a 2.1 (1.7, 2.6) times greater odds of new fracture in the upper spine, compared with 1.5 (1.3, 1.8) for the lower spine. These findings suggest that, in older women, osteoporosis may be a stronger risk factor for new fractures in the upper (vs. lower) thoracolumbar spine, although we found no evidence that the location of prior fractures should influence treatment decisions. Physicians should recognize that prior vertebral fractures are a strong risk factor for future fractures, and consider treating such patients to reduce their risk of subsequent fractures.