Primary amputation (ie, without attempted revascularization) is a devastating complication of peripheral artery disease. Racial disparities in primary amputation have been described; however, rural disparities have not been well investigated. The purpose of this study was to examine the impact of rurality on risk of primary amputation and to explore the effect of race on this relationship. The national Vascular Quality Initiative amputation data set was used for analyses (N = 6795). The outcome of interest was primary amputation. Independent variables were race/ethnicity (non-Latinx whites vs nonwhites) and rural residence. Multivariable logistic regression examined impact of rurality and race/ethnicity on primary amputation after adjustment for relevant covariates and included an interaction for race/ethnicity by rural status. Primary amputation occurred in 49% of patients overall (n = 3332), in 47% of rural vs 49% of urban patients (P = .322), and in 46% of whites vs 53% of nonwhites (P < .001). On multivariable analysis, nonwhites had a 21% higher odds of undergoing primary amputation overall (adjusted odds ratio [AOR], 1.21; 95% confidence interval [CI], 1.05-1.39). On subgroup analysis, rural nonwhites had two times higher odds of undergoing primary amputation than rural whites (AOR, 2.06; 95% CI, 1.53-2.78) and a 52% higher odds of undergoing primary amputation than urban nonwhites (AOR, 1.52; 95% CI, 1.19-1.94). In the urban setting, nonwhites had a 21% higher odds of undergoing primary amputation than urban whites (AOR, 1.21; 95% CI, 1.05-1.39). In these analyses, rurality was associated with greater odds for primary amputation in nonwhite patients but not in white patients. The effect of race on primary amputation was significant in both urban and rural settings; however, the effect was significantly stronger in rural settings. These findings suggest that race/ethnicity has a compounding effect on rural health disparities and that strategies to improve health of rural communities need to consider the particular needs of nonwhite residents to reduce disparities. Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.