Purpose <p>After surgery, beyond 150 pg/ml of calcitonin (ctn) in medullary thyroid cancer (MTC) patients, international recommendations suggest adding 6-[¹⁸F]fluoro-L-3,4-dihydroxyphenylalanine positron emission tomography ([¹⁸F]FDOPA PET/CT) to conventional imaging (CI). The aim of this study was to measure the impact of the [¹⁸F]FDOPA in the management of MTC patients.</p> Methods <p>This prospective, multicenter, study evaluated the benefit of [¹⁸F]FDOPA compared to CI. The primary endpoint was the relative true-positive rate of metastatic cervical lymph nodes in a per lymph node analysis. Secondary endpoints are discordance rate between [¹⁸F]FDOPA and CI, changes in patient management according to a board of experts and concordance between [¹⁸F]FDOPA reading in the investigating center and a centralized review.</p> Results <p>The study included 24 patients. The median ctn rate was 824 pg/mL (range 176-16418). Sixty lymph nodes were detected by [¹⁸F]FDOPA or CI, fifty-three were defined involved and 7 non-involved. [¹⁸F]FDOPA detected 1.5 (95% CI 1.25–1.84) times more metastatic lymph nodes compared to CI. For metastases, the discordance rate was 46.4% (95% CI 27.5–66.1). According to the tumor board, 14 patients (58.3%, 95%CI: 36.6–77.9) had a change in management after [¹⁸F]FDOPA results (monitoring or surgery or modified surgery or fine needle aspiration or local/ systemic treatment). The discordance rate for [¹⁸F]FDOPA reading was 20.8% (95%CI: 7.1–42.2, 5/24 patients).</p> Conclusion <p>In this multicenter prospective study, [¹⁸F]FDOPA is more effective than CI for detecting metastatic lymph nodes and would change management in 58% of cases. The [¹⁸F]FDOPA reading remains challenging and requires a learning curve in case of MTC.</p>