BACKGROUND: Radiotherapy of the left breast is associated with higher cardiovascular mortality linked to cardiotoxic effect of irradiation. Radiotherapy of inner quadrants can be associated with greater heart irradiation, but no study has evaluated the effect of inner-quadrant irradiation on cardiovascular mortality. PATIENTS AND METHODS: We identified 1245 women, the majority with breast-conserving surgery, irradiated for primary node-negative breast cancer from 1980 to 2004 registered at the Geneva Cancer Registry. We compared breast cancer-specific and cardiovascular mortality between inner-quadrant (n = 393) versus outer-quadrant tumors (n = 852) by multivariate Cox regression analysis. RESULTS: After a mean follow-up of 7.7 years, 28 women died of cardiovascular disease and 91 of breast cancer. Patients with inner-quadrant tumors had a more than doubled risk of cardiovascular mortality compared with patients with outer-quadrant tumors (adjusted hazard ratio 2.5; 95% confidence interval 1.1-5.4). Risk was particularly increased in the period with higher boost irradiation. Patients with left-sided breast cancer had no excess of cardiovascular mortality compared with patients with right-sided tumors. CONCLUSIONS: Radiotherapy of inner-quadrant breast cancer is associated with an important increase of cardiovascular mortality, a possible result of higher irradiation of the heart. For patients with inner-quadrant tumors, the heart should be radioprotected.