Vertebral fractures in older women signal an increased risk of additional osteoporotic fractures. To identify risk factors for first vertebral fractures, we studied 5822 women greater than or equal to65 years of age who had no fracture on baseline radiographs of the spine. Several modifiable risk factors increased an older woman's risk of developing a first vertebral fracture, and women with multiple risk factors and low BMD had the highest risk. Risk factors and low BMD should be useful to help focus efforts to prevent these fractures. Introduction: Vertebral fractures are a common cause of back pain and disability and signal an increased risk of additional osteoporotic fractures in older women. Little is known about the risk factors for the first occurrence of a vertebral fracture. Materials and Methods: To identify risk factors for a first vertebral fracture, we studied 5822 women greater than or equal to65 years of age from the Study of Osteoporotic Fractures who had no fracture on baseline radiographs of the spine. We measured potential risk factors and BMD of the wrist and calcaneus at baseline and BMD of the spine and hip halfway through follow-up. Fractures were assessed by standard methods from spine radiographs obtained at baseline and follow-up an average of 3.7 years later. Results and Conclusions: In multivariable analyses, older age, previous nonspine fracture, low BMD at all sites, a low body mass index (BMI), current smoking, low milk consumption during pregnancy, low levels of daily physical activity, having a fall, and regular use of aluminum-containing antacids independently increased the risk of a first vertebral fracture. Women using estrogen and those who engaged in recreational physical activity had a decreased risk. The effects of low BMI, smoking, use of estrogen and antacids, and previous fracture were partially mediated by BMD. Women in the lower third of wrist BMD with five or more risk factors had a 12-fold greater risk than women in the highest third of BMD who had zero to three risk factors. The 27% of women at highest risk suffered 60% of the incident fractures. In conclusion, several modifiable risk factors and BMD independently increase an older woman's risk of developing a first vertebral fracture. The combination of risk factors and BMD should be useful for focusing efforts to prevent vertebral fractures.