Purpose:To evaluate the effects of lung volume differences on apparent diffusion coefficient (ADC) measurements on a regional basis, with breath holds at volumes adjusted for differences in lung size across individuals according to the subject's vital capacity (VC).Materials and Methods:This study was approved by the local institutional review board and was compliant with HIPAA. Informed consent was obtained from all subjects. Imaging was performed under a physician's Investigational New Drug application from the Food and Drug Administration. ADC changes as a function of inflation levels were evaluated in 24 healthy never-smokers across three lung volumes (20%, 60%, and 100% VC) on the basis of the spirometric data collected from each subject. Response variables based on lung volume and anatomic position were assessed with multifactorial analysis of variance followed by posthoc pair-wise testing. Imaging was performed with a 1.5-T magnetic resonance (MR) unit with use of a two-dimensional gradient-echo fast low-angle shot sequence.Results:Significant differences in ADCs between lung volumes were observed for all inflation levels (20%, 60%, and 100% VC; P <.001), along with significant dependent-nondependent vertical gradients at 20% VC (P <.0001) and 60% VC (P <.0001, left lung only). In addition, significant differences between mean values in the left and right lungs with respect to those in the whole lung were observed at the lower lung inflation levels (20% and 60% VC, P <.01), reaching more uniform expansion at 100% VC.Conclusion:The results confirm known anatomic differences in patterns of regional inflation and ventilation with corresponding lung volume changes, emphasizing the need for tight control over lung volume when performing hyperpolarized helium 3 ((3)He) lung studies if (3)He MR imaging is to be used to follow up small longitudinal changes in lung abnormalities.© RSNA, 2013.