Background: The risk of secondary lung malignancy (SLM) is a concern for women treated with breast radiation therapy after breast conserving surgery for early stage breast cancer. The purpose of this study was to estimate the absolute and relative risks of developing secondary lung malignancies in patients treated either with supine or prone whole breast radiotherapy or with Mammosite brachytherapy. Methods: Twenty-two women treated with breast radiotherapy were enrolled in the study. Fifteen patients underwent CT simulation and standard fractionated and hypofractionated whole breast radiation treatment planning in both the prone and the supine positions. Seven patients underwent CT simulation and treatment planning for Mammosite brachytherapy. Dose-volume histograms of the ipsilateral breast and the lungs were calculated and incorporated into a biologically-based mathematical model of spontaneous and radiation-induced carcinogenesis to quantitatively predict the lifetime absolute and relative risks of secondary lung malignancies. Results: The average predicted absolute lifetime risk for SLMs for patients treated in the supine position was higher than that for patients treated in the prone position (4.9% vs. 2.0% respectively, 2-tailed paired t-test, p<0.00001). The risk for SLMs for supine breast irradiation was higher than that for Mammosite patients (4.9% vs. 3.1% respectively, 2-tailed independent two sample t-test, p<0.005). The average predicted absolute lifetime risk of SLMs associated with standard supine breast irradiation was more than three times higher than the predicted background lifetime risk of lung cancer for this population (4.9% vs. 1.3% respectively, 2-tailed independent two sample t-test, p<0.00001). The relative risk increased with younger patient age. Conclusions: Treatment with supine breast irradiation results in a greater predicted risk of developing secondary lung malignancies than treatment with Mammosite brachytherapy or prone breast irradiation. While Mammosite brachytherapy reduces the risk of SLMs, the largest risk reduction is with prone breast irradiation. Prone breast irradiation may reduce the incidence of SLMs in this patient population.