Abstract People with Li-Fraumeni syndrome harbor a germline pathogenic variant in the TP53 tumor suppressor gene; face a near 100% lifetime risk of cancer; and routinely undergo intensive surveillance protocols. Liquid biopsy has become an attractive tool for a range of clinical applications, including early cancer detection. Here, we provide a proof-of-principle for a multi-modal liquid biopsy assay that integrates a targeted gene panel, shallow whole genome, and cell-free methylated DNA immunoprecipitation sequencing for the early detection of cancer in a longitudinal cohort of 89 Li-Fraumeni syndrome patients. Multi-modal analysis increased our detection rate in patients with an active cancer diagnosis over uni-modal analysis; and was able to detect cancer-associated signal in carriers prior to diagnosis with conventional screening (PPV = 67.6%, NPV = 96.5%). While adoption of liquid biopsy into current surveillance will require further clinical validation, this study provides a framework for individuals with Li-Fraumeni syndrome.