As breast cancer survival improves, patients face the long-term consequences of the disease, its causes, and its treatment. The main objectives of this study were to investigate the relationship between cigarette smoking, radiation therapy, and the development of second primary lung cancer. We conducted a population-based nested case-control study of women who were listed in the Connecticut Tumor Registry as having a first primary breast cancer diagnosed from 1965–1989. Cases were those who developed a second primary cancer of the lung at least ten years after the first primary breast cancer diagnosis. Controls had survived at least as long as their case without being diagnosed with a second primary lung cancer. Medical records were abstracted for each case and control for information on history of cigarette smoking and breast cancer therapies. Unconditional logistic regression analysis was used to estimate odds ratios for the effects of cigarette smoking and RT, and their joint effects, on the risk of second primary lung cancer. Our sample included 119 cases and 380 controls; 68% of case patients had ever smoked cigarettes at the time of breast cancer diagnosis, compared with 26% of control patients. Current smokers at the time of breast cancer diagnosis were nearly 10 times more likely to develop a second primary lung cancer than never-smokers [OR = 9.70 (95% CI, 5.13–18.35)]. Assessment of potential interaction between smoking and RT resulted in an adjusted OR 26.25 for ever-smokers who received RT for their breast cancer (95% CI, 10.40–66.25). Polytomous regression models revealed that both RT and cigarette smoking had a greater effect in ipsilateral lung cancers compared to contralateral lung cancers. Smoking at the time of breast cancer diagnosis significantly increased the risk of lung cancer in this group of ≥10-year breast cancer survivors. Women who received RT as a part of their treatment for breast cancer were at much higher risk for a subsequent lung cancer if they were smokers than if they never smoked, did not receive RT, or had neither exposure.