Whole-genome association studies using single-nucleotide polymorphisms (SNPs) are the proposed method of choice for the identification of loci associated with complex diseases. In this report, we address the feasibility of generating high-density SNP maps (with <100-kb spacing). As a pilot study, we concentrated on a 4-Mb region around the human APOE locus on chromosome 19. We compared the efficiency of SNP detection using YAC-based versus BAC/PAC-based maps, sequencing individual DNAs versus a pooled DNA sample, and we evaluated three different software applications for polymorphism detection. A total of 121 SNPs (25 in coding regions) were identified. The frequency of SNP detection was 1 SNP/1.1 kb of genomic sequence. From APOE to CALM3 (approximately 2 Mb), the average marker spacing was approximately 30 kb. Fifty-one SNPs were genotyped in five populations, and 10 SNPs showed an allele frequency differential greater than 0.5 between populations. Our results demonstrated that high-density SNP maps can be efficiently generated using existing technologies and that a genome-wide map with 60,000-100,000 SNPs is achievable in a reasonable time frame.