Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS). Mutation carriers ascertained on family history have an extremely high lifetime risk of cancers arising from one or more of many possible sites. There is no established screening strategy for early detection and treatment of these cancers. Herein, we report preliminary data from a prospective study of a whole-body screening program that includes whole-body. Five new malignancies (3 de novo, 2 recurrent) have been identified in five of the first 30 participants, suggesting potentially significant benefits from screening in this population.