Contrast-enhanced CT has an important role in assessing liver lesions. However, the optimal protocol to get most effective result is not clear. The main goal when deciding injection protocol is to optimize lesion detectability with rapid scanning when lesion-to-liver contrast is maximum. For this purpose, we developed a physiological model of the contrast medium enhancement based on the compartment modeling and pharmacokinetics. Blood supply to liver is achieved in two paths. This dual supply characteristic distinguishes the CT enhancement of liver from that of the other organs. The first path is by hepatic artery and the second, by portal vein. However, it is assumed that only hepatic artery can supply blood to hepatocellular carcinoma (HCC) compartment, thus, the difference of contrast enhancement is resulted between normal liver tissue and hepatic tumor. By solving differential equations for each compartment simultaneously using the computer program Matlab, CT contrast-enhancement curves were simulated. The simulated enhancement curves for aortic, hepatic, portal vein, and HCC compartments were compared with the mean enhancement curves from 24 patients exposed to the same protocols as the simulation. These enhancement curves showed a good agreement. Furthermore, we simulated lesion-to- liver curves for various injection protocols, and the effects were analyzed. The variables to be considered in the injection protocol were injection rate, dose, and concentration of contrast material. These data may help to optimize scanning protocols for better diagnosis.