The purpose of this study was to evaluate whether ferumoxides-enhanced MR imaging of focal hepatic lesions provides distinctive signal intensity and lesion-to-liver contrast changes for benign and malignant lesions, helping to further characterize and differentiate these lesions. Data analysis was performed on 70 patients, with previously identified focal hepatic lesions, who underwent MR imaging of the liver before and after IV administration of ferumoxides (10 micromol Fe/kg). Lesions analyzed with pathologically proven diagnoses included metastases (n = 40), hepatocellular carcinoma (n = 11), cholangiocarcinoma (n = 6), hemangioma (n = 4), focal nodular hyperplasia (n = 6), and hepatocellular adenoma (n = 3). Response variables measured and statistically compared included the percentage of signal-intensity change and lesion-to-liver contrast. Focal nodular hyperplasia showed significant signal intensity loss on ferumoxides-enhanced T2-weighted images (mean, -43%+/-6.7%, p < 0.01). All other lesion groups showed no statistically significant change in signal intensity on ferumoxides-enhanced T2-weighted images, although signal intensity loss was seen in some individual hepatocellular adenomas (mean, -6.6%+/-24.0%) and hepatocellular carcinomas (mean, -3.3%+/-10.3%). All lesions, with the exception of hepatocellular carcinoma, had a marked increase in lesion-to-liver contrast on ferumoxides-enhanced T2-weighted images, which was statistically significant for metastases and hemangioma (p < 0.02). Focal nodular hyperplasia shows significant decrease in signal intensity on ferumoxides-enhanced T2-weighted images, which may aid in the differentiation of focal nodular hyperplasia from other focal hepatic lesions. Other lesions, namely, hepatocellular adenoma and carcinoma, can have reticuloendothelial uptake, but usually to a lesser degree than that of focal nodular hyperplasia.