Abstract Background Li‐Fraumeni Syndrome (LFS) is a rare cancer‐predisposing condition caused by germline mutations in TP53. Conventional wisdom and prior work has implied an increased risk of secondary malignancy in LFS patients treated with radiation therapy (RT); however, this risk is not well‐characterized. Here we describe the risk of subsequent malignancy and cancer‐related death in LFS patients after undergoing RT for a first or second primary cancer. Methods We reviewed a multi‐institutional hereditary cancer registry of patients with germline TP53 mutations who were treated from 2004 to 2017. We assessed the rate of subsequent malignancy and death in the patients who received RT (RT group) as part of their cancer treatment compared to those who did not (non‐RT group). Results Forty patients with LFS were identified and 14 received RT with curative intent as part of their cancer treatment. The median time to follow‐up after RT was 4.5 years. Fifty percent (7/14) of patients in the curative‐intent group developed a subsequent malignancy (median time 3.5 years) compared to 46% of patients in the non‐RT group (median time 5.0 years). Four of seven subsequent malignancies occurred within a prior radiation field and all shared histology with the primary cancer suggesting recurrence rather than new malignancy. Conclusion We found that four of14 patients treated with RT developed in‐field malignancies. All had the same histology as the primary suggesting local recurrences rather than RT‐induced malignancies. We recommend that RT should be considered as part of the treatment algorithm when clinically indicated and after multidisciplinary discussion.