The availability of large amounts of genomic DNA (gDNA) is the limiting factor for many of the molecular biology assays in genetic epidemiologic studies. Whole-genome amplification using multiple displacement amplification is used to amplify a representative sample of gDNA from small amounts of gDNA to optimize gDNA yield. We collected oral rinse DNA samples through the mail from 3,377 women enrolled in a population-based U.S. breast cancer case-control study and did whole-genome amplification by multiple displacement amplification. Genotyping was done for 66 single nucleotide polymorphisms (SNP) in 18 candidate susceptibility genes using amplified DNA with genomic replicates included for quality control. The concordance rates (percentages of agreement) in 95 quality control replicates of gDNA and amplified DNA for 66 SNPs ranged from 88% to 100% (median, 97%). The average allelic error rate was 0.9%. However, in further analyses based on the full control series (n = 1,492), >60% of the SNPs failed tests for Hardy-Weinberg equilibrium (P < 0.05), with evidence of heterozygote loss in the great majority. Even eliminating the 9% of samples with lower quality or input DNA, tests for Hardy-Weinberg equilibrium indicated persistent allele bias in nearly a third of the SNPs. Whole-genome amplification may introduce substantial allele amplification bias in gDNA collected using a common protocol in population-based epidemiologic studies.