BACKGROUND For periampullary adenocarcinoma, the histological subtype is a better prognostic predictor than the site of tumor origin. Intestinal-type periampullary adenocarcinoma (IPAC) is reported to have a better prognosis than the pancreatobiliary-type periampullary adenocarcinoma (PPAC). However, the classification of histological subtypes is difficult to determine before surgery. Apparent diffusion coefficient (ADC) histogram analysis is a noninvasive, nonenhanced method with high reproducibility that could help differentiate the two subtypes. AIM To investigate whether volumetric ADC histogram analysis is helpful for distinguishing IPAC from PPAC. METHODS Between January 2015 and October 2018, 476 consecutive patients who were suspected of having a periampullary tumor and underwent magnetic resonance imaging (MRI) were reviewed in this retrospective study. Only patients who underwent MRI at 3.0 T with different diffusion-weighted images (b-values = 800 and 1000 s/mm(2)) and who were confirmed with a periampullary adenocarcinoma were further analyzed. Then, the mean, 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles of ADC values and ADC(min), ADC(max), kurtosis, skewness, and entropy were obtained from the volumetric histogram analysis. Comparisons were made by an independent Student's t-test or Mann-Whitney U test. Multiple-class receiver operating characteristic curve analysis was performed to determine and compare the diagnostic value of each significant parameter. RESULTS In total, 40 patients with histopathologically confirmed IPAC (n = 17) or PPAC (n = 23) were enrolled. The mean, 5th, 25th, 50th, 75th, 90th, and 95th percentiles and ADC(max) derived from ADC(1000) were significantly lower in the PPAC group than in the IPAC group (P < 0.05). However, values derived from ADC(800) showed no significant difference between the two groups. The 75th percentile of ADC(1000) values achieved the highest area under the curve (AUC) for differentiating IPAC from PPAC (AUC = 0.781; sensitivity, 91%; specificity, 59%; cut-off value, 1.50 x 10(-3) mm(2)/s). CONCLUSION Volumetric ADC histogram analysis at a b-value of 1000 s/mm(2) might be helpful for differentiating the histological subtypes of periampullary adenocarcinoma before surgery.