Rationale and Objectives. The purpose of this study was to compare hepatic enhancement characteristics using two different contrast media injection protocols with multidetector helical computed tomography. Materials and Methods. Twenty-three patients with known or suspected liver lesions scheduled to undergo biphasic hepatic multidetector helical computed tomography were randomized into one of two groups: (1) 150 mL of iopamidol (300 mI/mL) at 5 mL/second, or (2) 100 mL of iopamidol (370 mgI/mL) at 4 mL/second. Unenhanced images were acquired initially, followed by both hepatic arterial phase (scan delay, 33 seconds) and portal venous phase (PVP; scan delay, 65 seconds) imaging. Three abdominal radiologists independently graded the images on a scale from 1-5 for enhancement and overall scan quality. Time-attenuation curves were generated from operator-defined region-of-interest measurements of liver parenchyma and aorta. Results. Qualitatively, the three reviewers found no significant difference between the two study groups in terms of overall scan quality (P = .23) or aortic enhancement (hepatic arterial phase, P = .9; PVP, P = .24). However, liver enhancement during the PVP was considered to be less in the Isovue 370 group (P = .04). Quantitatively, during the hepatic arterial phase, there was no statistically significant difference between the two injection protocols comparing either aortic or hepatic parenchymal enhancement (P = .62 and .80, respectively). During the PVP, these differences were statistically significant, with both aortic and hepatic parenchymal enhancement lower in the Isovue 370 group (P <.01 and P = .04, respectively). Conclusion. It is important to consider the amount of iodine injected per second and the duration of the injection when setting up protocols to achieve target organ enhancement. 100 mL of iopamidol 370 at 4 mL/second can be used to obtain images of the liver with good diagnostic quality compared to more conventional protocols using 150 mL of iopamidol 300 at 5 mL/second. However, the degree of liver parenchymal enhancement during the PVP using the latter injection scheme is lower, which in turn could potentially reduce hepatic lesion conspicuity.