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Purpose: To determine whether there are rural/urban differences in e-cigarette use and reasons for use that vary across the 10 Health & Human Services (HHS) regions., Methods: Age-adjusted bivariate and multivariable analyses were conducted for n = 225,413 respondents to the 2014-2015 Tobacco Use Supplement-Current Population Survey to estimate the prevalence of e-cigarette use. Reasons for e-cigarette use were collected from n = 16,023 self-respondents who reported ever using e-cigarettes., Findings: While nationally rural residents appeared more likely to use e-cigarettes, adjusted results indicated that current e-cigarette use was significantly less likely across the northern and western regions (New England, East North Central, Heartland, North Central Mountain, Northwest, and Southwest Pacific regions). Reasons for e-cigarette use differed by urban/rural status and region; for example, the rationale to use e-cigarettes as a smoking cessation aid was significantly more common among rural compared to urban adults in the New England and New York/New Jersey regions, but less common in the Southeast., Conclusions: For several regions, there were no significant rural/urban differences in e-cigarette use and reasons for use. Yet those regions that present differences face the need to develop public health approaches to minimize urban/rural disparities in health education, services, and outcomes related to tobacco use, particularly where access to health care is limited. Public health campaigns and guidance for clinical care within HHS regions should be tailored to reflect regional differences in beliefs about e-cigarettes., (© 2018 National Rural Health Association.)