Background: This study was conducted to investigate whether apparent diffusion coefficient (ADC) measurements by dividing the liver into left and right hepatic lobes may be utilized to improve the accuracy of differential diagnosis of benign and malignant focal liver lesions. Materials and Methods: A total of 269 consecutive patients with 429 focal liver lesions were examined by 3-T magnetic resonance imaging that included diffusion-weighted imaging. For 58 patients with focal liver lesions of the same etiology in left and right hepatic lobes, ADCs of normal liver parenchyma and focal liver lesions were calculated and compared using the paired t-test. For all 269 patients, ADC cutoffs for focal liver lesions and diagnostic accuracy in the left hepatic lobe, right hepatic lobe and whole liver were evaluated by receiver operating characteristic curve analysis. Results: For the group of 58 patients, mean ADCs of normal liver parenchyma and focal liver lesions in the left hepatic lobe were significantly higher than those in the right hepatic lobe. For differentiating malignant lesions from benign lesions in all patients, the sensitivity and specificity were 92.6% and 92.0% in the left hepatic lobe, 94.4% and 94.4% in the right hepatic lobe, and 90.4% and 94.7% in the whole liver, respectively. The area under the curve of the right hepatic lobe, but not the left hepatic lobe, was higher than that of the whole liver. Conclusions: ADCs of normal liver parenchyma and focal liver lesions in the left hepatic lobe were significantly higher than those in the right hepatic lobe. Optimal ADC cutoff for focal liver lesions in the right hepatic lobe, but not in the left hepatic lobe, had higher diagnostic accuracy compared with that in the whole liver.