Background: Ionizing radiation is a well-established human mammary carcinogen. Women historically monitored by radiography at young ages for abnormal spinal curvature are an exposed population suitable for investigating radiation-related risk and its variation by modifying factors. In this historic cohort, 95% of daily dose increments (when exposure to the breast occurred) were under 2.4 cGy, with mean 1.1 cGy. Methods: A retrospective cohort of 3,010 women, diagnosed with spinal curvature between 1912 and 1965 in 14 U.S. pediatric orthopedic centers and who completed a questionnaire by telephone interview or mail survey in 1992, were studied for risk of breast cancer by radiation dose to the breast (mean, 12 cGy) after adjustment for established breast cancer risk factors. Results: A borderline-significant radiation dose response (excess relative risk/Gy = 2.86; P = 0.058; one-tailed P = 0.029) was observed during 118,905 woman-years of follow-up (median, 35.5 years) based on 78 cases of invasive breast cancer. The dose response was significantly greater (P = 0.03) for women who reported a family history of breast cancer in first- or second-degree relatives (excess relative risk/Gy = 8.37; 95% confidence interval, 1.50-28.16). Radiation-related risk did not vary significantly by stage of reproductive development at exposure. Conclusions: Assuming that repair of radiation-related DNA damage requires at most a few hours, our data argue against existence of a low-dose threshold on the order of 1 to 3 cGy for radiation exposure contributing to breast carcinogenesis. The possibility that a family history of breast cancer may have enhanced a carcinogenic radiation effect requires confirmation in other studies.