Objectives: The aim of this study was to examine the association between maternal high-risk factors and anemia among reproductive-age women in Ethiopia. Methods: A cross-sectional study was conducted using data from the 2016 Ethiopia Demographic and Health Survey (N = 5282). Hemoglobin levels were used to determine anemia status. Maternal high-risk factors were measured using maternal age at delivery, birth order, and birth interval. We performed chi(2) test and multivariable regression models. Results: There was a significant antagonistic interaction between maternal high-risk factors and place of residence on anemia (relative excess risk due to interaction, -1.79, synergy index, 0.48) with an attributable proportion due to interaction (AP) of -67% (AP = -0.67; 95% confidence interval [CI], -0.95 to -0.29). Multiplicative interaction was also significant (odds ratio for interaction, 0.38; P = 0.003). The odds of anemia were higher among women with any maternal high-risk factor than in those who did not experience any high-risk factors (adjusted odds ratio [AOR], 2.64; 95% CI, 1.24-5.63 for urban and AOR, 1.27; 95% CI, 1.01-1.61 for rural women). Exposure to a single maternal high-risk factor was significantly associated with increased odds of anemia among urban residents only (AOR, 2.61; 95% CI, 1.17-5.81). Exposure to multiple maternal high-risk factors significantly increased the odds of anemia (AOR, 2.82; 95% CI, 1.15-6.91) and (AOR, 1.55; 95% CI, 1.10-2.17) for urban and rural women, respectively. Conclusions: Place of residence moderated the relationship between maternal high-risk factors and anemia. Context-specific strategies and interventions are needed to prevent anemia. (C) 2021 Elsevier Inc. All rights reserved.