The purpose of this study was to determine the diagnostic performance of chemical shift imaging, compared with that of single-echo T2*-weighted imaging, for hepatic iron quantification in patients with liver disease, and to examine the confounding effect of steatosis. Sixty-three patients who underwent liver MRI and who had concomitant liver histopathologic analysis were retrospectively assessed. Chemical shift imaging and T2*-weighted imaging (n = 49) of the liver were reviewed by two independent observers. An iron index for each sequence (I(Fe-CSI) and I(Fe-T2*), respectively) was correlated with pathologic iron grade (0-4). Receiver operating characteristic curve analysis was performed to assess the accuracy of both sequences for the diagnosis of iron deposition (grades >or= 1, >or= 2, and >or= 3), and the impact of steatosis on accuracy was evaluated. Forty-seven (74.6%) patients had hepatic siderosis. There was a significant correlation between both I(Fe-CSI) and I(Fe-T2*) with pathologic iron grade (r = 0.65 and -0.61, respectively; p < 0.0001 for both). I(Fe-CSI) and I(Fe-T2*) were significantly higher or lower in iron grades 2-4 versus grades 0-1 and in grades 3-4 versus grades 0-2 (p < 0.001). Area under the curve values for detecting iron grade >or= 1, >or= 2, and >or= 3 were 0.75, 0.88, and 0.90 for I(Fe-CSI) and 0.72, 0.81, and 0.98 for I(Fe-T2*). Accuracy was lower for both sequences in steatotic patients for detection of iron grades >or= 1 and >or= 2, without reaching significance. Routine chemical shift imaging and single-echo T2*-weighted imaging have excellent diagnostic performance for detection of significant hepatic siderosis (grade >or= 2). Concomitant steatosis lowers the diagnostic performance of both sequences without reaching significance.