Background: Women with a history of ductal carcinoma in situ (DCIS) are at increased risk for developing a second breast cancer (SBC). A prior meta-analysis of randomized studies of radiotherapy (RT) for DCIS has shown a trend toward increased breast cancer–specific mortality after SBC, but it did not have the power needed to detect a significant difference, due to a limited number of recurrences. This study sought to evaluate the impact of RT for DCIS on mortality after SBC in a larger cohort. Patients and Methods: Using the SEER database, 3,407 patients were identified who received breast-conserving therapy with or without RT for primary DCIS in 2000 through 2013 and subsequently developed a stage I–III invasive SBC within the same time period. Fine-Gray competing risk models were used to study the association between receipt of RT and mortality after SBC. Results: Prior RT was found to be associated with higher rates of breast cancer–specific mortality (hazard ratio [HR], 1.70; 95% CI, 1.18–2.45; P=.005), even after controlling for cancer stage. Interaction analysis suggested that this risk trended higher in patients with ipsilateral versus contralateral SBC (HR, 2.07 vs 1.26; P=.16). Furthermore, compared with patients who developed contralateral SBC, those with ipsilateral SBC were younger (P<.001) and more often lacked estrogen receptor expression (P<.001). Conclusions: Patients who previously received RT for DCIS had higher mortality after developing an invasive SBC than those who did not receive RT. This finding may have implications for initial treatment decisions in the management of DCIS.