Objectives <p>Annual whole-body MRI (WB-MRI) is recommended for early cancer detection in individuals with Li-Fraumeni syndrome (LFS). However, there is no agreement on a standardized MRI protocol. This study evaluated the diagnostic performance of different MRI sequences to suggest an optimized protocol for LFS surveillance.</p> Materials and methods <p>In this prospective bicentric study, 113 participants with LFS underwent annual WB-MRI and were included in the analysis. The protocol comprised turbo-spin echo (TSE) T1-weighted and inversion-recovery T2-weighted (TIRM) images of the whole body in coronal orientation, and T2-weighted (HASTE), diffusion-weighted (DWI), and T1-weighted DIXON images (pre- and post-contrast agent administration) from head to thighs in axial orientation. An additional fluid-attenuated inversion recovery (FLAIR) sequence imaged the skull only. Initial clinical interpretation was conducted by staff radiologists. The visibility of reported mass lesions was independently graded in all sequences by three experienced radiologists using a Likert scale. Sequence combinations were compared to inform the design of an optimal MRI protocol.</p> Results <p>Over 30 months, 189 WB-MRI examinations were performed in 113 participants (mean age 40 years, ±12.7 years [standard deviation], 91 women). 188 mass lesions were detected and confirmed as malignant (<i>n</i> = 38), benign (<i>n</i> = 120) or ambiguous (<i>n</i> = 30). In the multi-reader analysis, all new malignant lesions could have been detected by a combination of cranial FLAIR, whole-body DWI, and whole-body HASTE in the axial direction.</p> Conclusion <p>A shortened, contrast-agent-free WB-MRI protocol combining cranial FLAIR, WB-HASTE, and WB-DWI promises to be an effective and patient-friendly approach for annual cancer surveillance in LFS.</p> Key Points <p><Emphasis Type="BoldItalic">Question</Emphasis> <i>Annual whole-body MRI (WB-MRI) is recommended for early cancer detection for individuals with Li-Fraumeni syndrome (LFS), but a standardized sequence protocol has yet to be established</i>.</p> <p><Emphasis Type="BoldItalic">Findings</Emphasis> <i>The combination of cranial FLAIR, whole-body HASTE, and whole-body DWI in the axial plane enabled visualization of all newly developed malignant lesions in our study cohort</i>.</p> <p><Emphasis Type="BoldItalic">Clinical relevance</Emphasis> <i>A shortened, standardized WB-MRI protocol enables efficient, sensitive early cancer detection in individuals with LFS, minimizing patient burden by reducing examination time and contrast agent use. This approach may improve surveillance participation while enhancing comparability across centers</i>.</p> Graphical Abstract <p></p>