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SummaryDespite advances in cancer therapeutics, early detection is often the best prognostic indicator for survival (1). People with Li-Fraumeni syndrome harbor a germline pathogenic variant in the tumor suppressor geneTP53(2) and face a near 100% lifetime risk of developing a wide spectrum of, often multiple, cancers (3).TP53mutation carriers routinely undergo intensive surveillance protocols which, although associated with significantly improved survival, are burdensome to both the patient and the health care system (4). Liquid biopsy, the analysis of cell-free DNA fragments in bodily fluids, has become an attractive tool for a range of clinical applications, including early cancer detection, because of its ability to provide real-time holistic insight into the cellular milieu (5). Here, we assess the efficacy of 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 cohort of Li-Fraumeni syndrome patients: 196 blood samples from 89 patients, of which 26 were pediatric and 63 were adults. Our integrated analysis was able to detect a cancer-associated signal in 79.4% of samples from patients with active cancer, a 37.5% – 58.8% improvement over each individual analysis. Through analysis of patient plasma at cancer negative timepoints, we were able to detect cancer-associated signals up to 16 months prior to occurrence of cancer as detected by conventional clinical modalities in 17.6% ofTP53mutation carriers. This study provides a framework for the integration of liquid biopsy into current surveillance methods for patients with Li-Fraumeni syndrome.