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Background: Imprinted genes are defined by their preferential expression from one of the two parental alleles. This unique mode of gene expression is dependent on allele-specific DNA methylation profiles established at regulatory sequences called imprinting control regions (ICRs). These loci have been used as biosensors to study how environmental exposures affect methylation and transcription. However, a critical unanswered question is whether they are more, less, or equally sensitive to environmental stressors as the rest of the genome. Objectives: Using cadmium exposure in humans as a model, we aimed to determine the relative sensitivity of ICRs to perturbation of methylation compared to similar, nonimprinted loci in the genome. Methods: We assayed DNA methylation genome-wide using bisulfite sequencing of 19 newborn cord blood and 20 maternal blood samples selected on the basis of maternal blood cadmium levels. Differentially methylated regions (DMRs) associated with cadmium exposure were identified. Results: In newborn cord blood and maternal blood, 641 and 1,945 cadmium-associated DMRs were identified, respectively. DMRs were more common at the 15 maternally methylated ICRs than at similar nonimprinted loci in newborn cord blood (p=5.64×10−8) and maternal blood (p=6.22×10−14), suggesting a higher sensitivity for ICRs to cadmium. Genome-wide, Enrichr analysis indicated that the top three functional categories for genes that overlapped DMRs in maternal blood were body mass index (BMI) (p=2.0×10−5), blood pressure (p=3.8×10−5), and body weight (p=0.0014). In newborn cord blood, the top three functional categories were BMI, atrial fibrillation, and hypertension, although associations were not significant after correction for multiple testing (p=0.098). These findings suggest that epigenetic changes may contribute to the etiology of cadmium-associated diseases. Conclusions: We analyzed cord blood and maternal blood DNA methylation profiles genome-wide at nucleotide resolution in individuals selected for high and low blood cadmium levels in the first trimester. Our findings suggest that ICRs may be hot spots for perturbation by cadmium, motivating further study of these loci to investigate potential mechanisms of cadmium action. https://doi.org/10.1289/EHP2085