Background Imaging assessment for hepatomegaly is not well defined and currently uses suboptimal, unidimensional measures. Liver volume provides a more direct measure for organ enlargement. Purpose To determine organ volume and to establish thresholds for hepatomegaly with use of a validated deep learning artificial intelligence tool that automatically segments the liver. Materials and Methods In this retrospective study, liver volumes were successfully derived with use of a deep learning tool for asymptomatic outpatient adults who underwent multidetector CT for colorectal cancer screening (unenhanced) or renal donor evaluation (contrast-enhanced) at a single medical center between April 2004 and December 2016. The performance of the craniocaudal and maximal three-dimensional (3D) linear measures was assessed. The manual liver volume results were compared with the automated results in a subset of renal donors in which the entire liver was included at both precontrast and postcontrast CT. Unenhanced liver volumes were standardized to a postcontrast equivalent, reflecting a correction of 3.6%. Linear regression analysis was performed to assess the major patient-specific determinant or determinants of liver volume among age, sex, height, weight, and body surface area. Results A total of 3065 patients (mean age ± standard deviation, 54 years ± 12; 1639 women) underwent multidetector CT for colorectal screening (n = 1960) or renal donor evaluation (n = 1105). The mean standardized automated liver volume ± standard deviation was 1533 mL ± 375 and demonstrated a normal distribution. Patient weight was the major determinant of liver volume and demonstrated a linear relationship. From this result, a linear weight-based upper limit of normal hepatomegaly threshold volume was derived: hepatomegaly (mL) = 14.0 × (weight [kg]) + 979. A craniocaudal threshold of 19 cm was 71% sensitive (49 of 69 patients) and 86% specific (887 of 1030 patients) for hepatomegaly, and a maximal 3D linear threshold of 24 cm was 78% sensitive (54 of 69) and 66% specific (678 of 1030). In the subset of 189 patients, the median difference in hepatic volume between the deep learning tool and the semiautomated or manual method was 2.3% (38 mL). Conclusion A simple weight-based threshold for hepatomegaly derived by using a fully automated CT-based liver volume segmentation based on deep learning provided an objective and more accurate assessment of liver size than linear measures. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Sosna in this issue.