Background: Multi-cancer Early Detection tests (MCED) and whole-body imaging are being increasingly utilized for early cancer detection but are not included in cancer screening guidelines. Our aims were to 1) determine the feasibility of MCED testing and whole-body MRI (WBM) to screen people at high-risk for cancer after germline testing and cancer genetics evaluation and 2) understand the impact of MCED and WBM on cancer worry and anxiety. Methods: We conducted a feasibility trial of people >50 years old with a strong family history of cancer and/or a pathogenic/likely pathogenic germline variant in a cancer susceptibility gene for which WBM is not part of standard risk management. Participants completed a baseline survey including the SF12, State Trait Anxiety Index (STAI), and modified cancer worry scale (CWS). They then underwent non-contrast whole body 3T MRI and liquid biopsy using DEEPGEN, a mutational-based MCED. Results were reported to participants and additional imaging studies or consultations were obtained as needed. Participants were surveyed 6 months after testing using SF12, STAI, CWS, and a questionnaire on acceptability of the intervention. Results: 100 participants were enrolled; 73 have completed 6-month follow-up. Median age was 62 years (IQR 57-66) and 64% of participants were women. MCED was positive in 4 participants, none of which had suspicious findings on WBM. 27 (27%) underwent additional imaging to further evaluate findings identified on WBM. 4 (4%) had cancer diagnosed based on WBM findings and subsequent work up (lung adenocarcinoma, prostate cancer, duodenal neuroendocrine carcinoma, and ovarian Brenner tumor); all 4 underwent surgical resection. One participant underwent bone marrow biopsy due to JAK2 mutation and thrombocytosis (evaluation ongoing) and one participant had a thyroid biopsy for a benign nodule. 62 (85%) somewhat/strongly agreed that study participation reduced cancer worry. Composite CWS scores showed decreased worry at 6 months compared with baseline (12.7 vs 13.7, p=0.003). At baseline, 30 (41%) reported that they somewhat/very often worry about getting cancer, compared with 14 (18%) at 6 months (p<0.001). 8 (11%) reported at baseline that cancer worry affected their mood somewhat/very often, compared with 2 (3%) at 6 months (p<0.001). There were no significant differences in STAI or SF12 composite scores between baseline and 6 months. 69 (95%) somewhat/strongly agreed that they would like to participate in future testing with WBM and MCED. Conclusions: MCED and WBM testing is feasible and was associated with decreased cancer worry at 6 months. In this high-risk cohort, cancer was detected in 4% of patients. Further evaluation of cancer screening in high-risk populations using WBM and MCED testing is warranted particularly with respect to patient-centered outcomes, cancer outcomes, and healthcare resource utilization. Clinical trial information: NCT05868486.