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BACKGROUND Smoking and alcohol consumption are potential risk factors for breast cancer (BC) and may modify the risk of radiotherapy-associated second primary cancer (SPC) occurrence and total mortality. We explored the joint effect of smoking, or alcohol drinking, and radiotherapy on the risk of SPC and overall mortality among BC survivals. METHODS We conducted a cancer registry-based study of 10,676 BC cases (stage 0-III) with data on smoking and alcohol consumption at time of diagnosis and clinical and therapeutics characteristics. Multivariable Cox proportional hazard models were used to estimate Hazard Ratios [HRs] and 95% confidence interval [CI] of total and site-specific SPC and mortality adjusting for demographic and cancer related characteristics. RESULTS The SPC risk associated with radiotherapy was higher among ever-smokers than never-smokers (p for interaction = 0.04). Compared to never-smokers/unirradiated, the adjusted HR for ever-smokers/irradiated was 1.79 (95%CI, 1.43-2.23), and for never-smokers/irradiated was 1.31 (95%CI, 1.06-1.63). Analysis by cancer site showed that for ever-smokers/irradiated the risk for hematological, gastrointestinal, gynecological urological and lung/pulmonary cancer was significantly increased by two to five-fold. Mortality was significantly higher for ever-smokers/irradiated (HR = 1.25; 95%CI, 1.06-1.47), but was lower for never-smokers/irradiated (HR = 0.85; 95%CI, 0.73-0.99). Alcohol consumption did not alter the association between radiotherapy and SPC risk, but was associated with lower mortality risk. CONCLUSION Patients who received radiotherapy and smoked before or at time of BC diagnosis have an increased risk for specific SPCs; drinking alcohol did not alter the effect of radiotherapy. Smoking significantly increased mortality risk reducing the protective effect of radiotherapy treatment.