BACKGROUND: Radiotherapy for breast cancer reduces disease recurrence and breast cancer mortality. However, it has also been associated with increased second cancer risks in exposed sites. METHODS: We evaluated long-term second cancer risks among 182 057 5-year survivors of locoregional invasive breast cancer diagnosed between 1973 and 2000 and reported to US NCI-SEER Program cancer registries. Multivariate Poisson regression was used to estimate the relative risk (RR) and excess cases of second cancer in women who had surgery and radiotherapy, compared with those who had surgery alone. Second cancer sites were grouped according to doses received from typical tangential breast fields. RESULTS: By the end of 2005 (median follow-up ¼ 13.0 years), 15 498 second solid cancers had occurred, including 6491 contralateral breast cancers. The RRs for radiotherapy were 1.45 (95% confidence interval (CI) ¼ 1.33 -1.58) for high-dose second cancer sites (1 þ Gy: lung, oesophagus, pleura, bone and soft tissue) and 1.09 (1.04 -1.15) for contralateral breast cancer (E1 Gy). These risks decreased with increasing age and year of treatment. There was no evidence of elevated risks for sites receiving medium (0.5 -0.99 Gy, RR ¼ 0.89 (0.74 -1.06)) or low doses (o0.5 Gy, RR ¼ 1.01 (0.95 -1.07)). The estimated excess cases of cancer in women treated with radiotherapy were as follows: 176 (95% CI ¼ 69 -284) contralateral breast cancers or 5% (2 -8%) of the total in all 1 þ year survivors, and 292 (222 -362) other solid cancers or 6% (4 -7%) of the total. CONCLUSIONS: Most second solid cancers in breast cancer survivors are not related to radiotherapy.