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To compare the diagnostic value of gadolinium (Gd) and ultrasmall superparamagnetic iron oxide (SPIO) contrast media for characterization of focal liver lesions (FLL), we retrospectively evaluated the results of magnetic resonance (MR) imaging in 68 patients (40 M, 28 F, age from 22 to 81 yrs) of which 36 with diagnosis of colo-rectal cancer, 26 with hepatic cirrhosis and 6 with incidental imaging detection of FLL. MR (Gyroscan Intera 1.5 T, Philips Medical Systems) study was performed using T1 and T2 fast-field-echo (FFE) and T2 turbo-spin-echo (TSE) sequences in axial and coronal views. Dynamic multi-phases gadolinium Gd-enhanced T1-FFE-Bh images were obtained in arterial, portal and equilibrium phases, followed by SPIO-enhanced T2-FFE scans. A qualitative analysis of pre- and post-contrast MR images to classify FLL as benign or malignant was performed using a 3-point scoring system: 0= benign; 1= suspicious for malignancy; 2= malignant. A total of 118 lesions were evaluated. In particular, histology (n=18), cytology (n=14) or clinical-imaging follow-up data (n=86) demonstrated 4 adenomas, 29 cysts, 3 focal steatosis, 25 hemangiomas, 1 focal vascular abnormality, 5 fibrotic lesions as well as 13 regenerative nodules, 6 dysplastic, 14 hepatocellular carcinomas (HCC), 17 metastasis and 1 cholangiocarcinoma. For MR imaging, diagnostic accuracy, sensitivity, specificity, positive (PPV) and negative (NPV) predictive values of Gd vs. SPIO images were respectively 83% vs. 92%, 79% vs. 74%, 85% vs. 99% (P=0.002), 68% vs. 96% (P=0.005) and 91% vs. 90%, respectively. The results suggest that SPIO-MR provides a diagnostic incremental value, as specificity and PPV, particularly to characterize FLL compared to Gd-MR; thus, we strongly recommend the use of SPIO when liver lesion characterization is requested and Gd images are uncertain.