PURPOSE: To prospectively compare the accuracy of gadofluorine M with that of monocrystalline iron oxide nanoparticle (MION)-47 for the depiction of cervical lymph node metastases at magnetic resonance (MR) imaging in a rabbit model of head and neck cancer by using histologic analysis as the reference standard. MATERIALS AND METHODS: Experiments were approved by the animal care committee. VX2 carcinomas were implanted in both ears of 11 rabbits 4 weeks before MR imaging. T2-weighted, T2*-weighted, and T1-weighted MR images were acquired, and sequential T1-weighted MR imaging was performed immediately and 30 minutes after administration of gadofluorine M (0.05 mmol gadolinium per kilogram body weight). T2-weighted and T2*-weighted MR imaging were performed 24 hours after administration of MION-47 (2.6 mg iron per kilogram body weight). Gadofluorine M- and MION-47-enhanced MR imaging were performed separately and independently by two radiologists who had no knowledge of histopathologic results, and the presence of metastases in lymph nodes was evaluated. A receiver operating characteristic analysis was conducted to compare the diagnostic value of gadofluorine M- and MION-47-enhanced MR imaging. RESULTS: Metastases were confirmed in 20 of 77 lymph nodes at histopathologic analysis. The area under the curve was significantly greater for gadofluorine M-enhanced MR imaging (0.997 and 0.981 for readers 1 and 2, respectively) than for MION-47-enhanced MR imaging (0.889 and 0.846 for readers 1 and 2, respectively). For gadofluorine M-enhanced MR imaging, sensitivity was 100% for both readers and specificity was 89.5% for reader 1 and 87.7% for reader 2. For MION-47-enhanced MR imaging, sensitivity was 80.0% for both readers and specificity was 75.4% for reader 1 and 71.9% for reader 2. CONCLUSION: Gadofluorine M-enhanced MR imaging has higher accuracy for depicting lymph node metastases than does MION-47-enhanced MR imaging.