Background: Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome primarily caused by germline TP53 mutations. LFS is associated with very high lifetime cancer risk and early onset of a wide range of cancers. Cancer surveillance is challenging given the tumor spectrum, although an MRI-based regimen has shown promise. An important aim of NCI’s LFS cohort study (NCT01443468) is to establish an effective cancer-screening regimen. Methods: Individuals with a germline TP53 mutation were eligible for screening with annual rapid sequence whole-body (WB) MRI, brain MRI, and breast MRI if applicable, colonoscopy every 3 years, and blood tests every 4 months; children < 17 years also have abdominal ultrasound every 4 months. Here we report the findings at baseline screening of the first 100 participants. Results: Twenty of the 100 WB MRIs had abnormalities requiring additional imaging. Subsequent biopsies in 3 individuals led to the diagnosis of 1 stage Ib lung cancer and 1 osteosarcoma. Of the brain MRIs, 1 required additional imaging, 1 required a 6-month follow-up brain MRI, 1 showed abnormalities consistent with Multiple Sclerosis in an asymptomatic individual, 1 was positive for a frontal lobe Grade II astrocytoma, and 1 showed a small thalamic lesion with a biopsy positive for pilocytic astrocytoma. Fifteen participants had breast MRI; 2 required 6-month follow-up breast MRI, and 2 required biopsies which were found to be DCIS. None of the labs or abdominal ultrasounds showed any abnormalities. A gastric cancer was diagnosed 8 months after a negative baseline screening in a 68 year-old woman. All cancers detected were completely resected, except the pilocystic astrocytoma, which is being closely monitored. Conclusions: Of the first 100 participants enrolled in the LFS cancer screening protocol, there were 6 prevalent and 1 interval cancers; we did not expect WB MRI to detect gastric cancer. Most abnormalities identified on baseline WB MRI (18/20) did not lead to a cancer diagnosis. The frequency of false-positive MRI findings should decrease with subsequent screening. The NCI cancer screening protocol is well-tolerated and showed promise in early cancer detection. Annual screening is on-going.