10578 Background: Li Fraumeni Syndrome (LFS) is a high penetrance multi-organ cancer predisposition syndrome, associated with a significant lifetime risk of developing cancer. The Surveillance study in Multi-Organ Cancer prone syndromes (SMOC+) is investigating the utility of annual surveillance, with inclusion of whole-body magnetic resonance imaging (WBMRI), for hereditary cancer syndromes without well-established risk management strategies. Here we report the long-term clinical and psychosocial outcome of surveillance in participants with LFS. Methods: Multimodality surveillance in this multi-centre, prospective, longitudinal, observational study for adult participants with LFS included annual clinic review and examination, WBMRI, breast MRI (MRIB), full blood count, prostate specific antigen; 2-5 yearly gastro-intestinal endoscopy and faecal occult blood test in intervening years. Quantitative psychometric evaluations were requested at regular intervals each year using Hospital Anxiety and Depression Scale (HADS), the Impact of Events scale anchored to cancer (IES-C), and the Impact of Events scale MRI (IES-MRI). Results: From July 2013 to December 2021, 132 (67% female) participants were enrolled at a median age of 36 (range 18-69 )years. There were 116 prior diagnoses of neoplasms among 68 (52%) participants, including 27 (20%) with multiple primaries. At a median follow up of 4 years, 46 new primary malignancies were diagnosed in 30 (23%) individuals, with median age at diagnosis of 43 (range 24-71 years). Four (3%) individuals developed recurrence of a prior malignancy. The malignancies were detected as a result of WBMRI (27), MRIB (7), gastroscopy (1), colonoscopy (1) and clinical review and examination (17). The most frequent new primaries were leiomyosarcoma and breast cancer (Table). Overall, 22 (17%) are not currently participating due to cancer related death (10), active cancer (6) or other life events (6). At 4 years after enrollment, 94, 80 and 50 participants completed at least one HADS (463 unique observations), IES-C (362 unique observations), and IES-MRI (268 unique observations) questionnaire, respectively. Controlling for demographic and cancer history variables, there was no evidence of changes in overall anxiety or depression (p=0.2), nor in degrees of distress associated with cancer (p=0.06) or WBMRI (p=0.6) over time. Conclusions: In LFS, annual surveillance with WBMRI is feasible and well tolerated, with no difference in distress experienced in the longer term. Over 80% of participants continue to engage with surveillance. The majority of cancer-affected individuals were able to resume surveillance after management of early disease. [Table: see text]