Background: Patients with Li-Fraumeni syndrome (LFS) are predisposed to a 90% lifetime risk of cancer, thus undergoing extensive cancer surveillance. While thyroid cancer is not a core LFS-associated malignancy, increased incidence of thyroid carcinoma has been reported within the LFS tumor spectrum. In the general population, thyroid cancer incidence has soared mainly via incidental detection. We investigated the rate of thyroid carcinoma in relation to p53 mutational process and increased screening. Methods: A retrospective chart review was conducted for clinico-pathological features for adult carriers of confirmed germline TP53 variants at three tertiary cancer centers. Standardized incidence ratio (SIR) was calculated using age, sex, and year-specific expected incidence rates of thyroid cancer from Surveillance, Epidemiology, and End Results (SEER) 1975 – 2020 data. Results: Among 600 patients from 400 families with LFS, 39 (6.5%) patients from 36 (9%) families developed thyroid carcinoma at an average age of 42 years (median = 40, ranged from 23 to 70 years of age). The majority of LFS patients with thyroid carcinoma were female (N=30, 77%). Thyroid carcinoma was the presenting cancer diagnosis in 17 (44%) patients. Over 70% of thyroid carcinoma diagnoses (N=31) were detected incidentally either via LFS cancer screening (N=12, 39%) or via an imaging study unrelated to LFS screening (N=10, 32%). All 39 thyroid carcinomas were of follicular cell origin (non-medullary), most were multifocal (67% of N=32), and 30% had nodal metastasis (N=10 of 33). Of 35 tumors with histologic data, papillary carcinoma (papillary, follicular, and tall cell subtypes) was most common (N=29, 83%), followed by follicular carcinoma (N=4, 11%) and oncocytic carcinoma (N=2, 6%). LFS patients most often underwent a total thyroidectomy (N=27, 69%) compared to a hemithyroidectomy (N=10, 26%) or hemithyroidectomy with completion surgery within three months (N=2, 5%). Intermediate to high risk of recurrence based on tumor characteristics was noted in 17 patients (44%), warranting consideration of radioactive iodine (RAI) therapy, including tall cell subtype (N=3), oncocytic or follicular histology, incomplete resection (N=2), extrathyroidal extension (N = 6), and greater than five positive lymph nodes (N=6). Five (29%) of these 17 patients received RAI. The SIR for thyroid carcinoma in LFS compared to SEER was 13 (95% CI 9.2-17.8, p<0.0001). The SIR was elevated for LFS patients diagnosed with thyroid carcinoma both prior to and after genetic testing (SIR 9.0, CI 5.3-14.2, p<0.0001 and SIR 20, CI 12.2- 30.9, p<0.0001, respectively). Conclusions: In this multi-institutional cohort, a 6-9% prevalence rate of thyroid carcinoma was observed in LFS patients and families, with >70% of the tumors identified incidentally. The rate of thyroid carcinoma in LFS is significantly elevated over the general population.