We generated a high-resolution genetic linkage map of the pericentromeric region of the human X chromosome from approximately Xp11.4 to Xq22. This map contains 41 loci defined by 50 marker systems genotyped in the CEPH families. For this study we have generated 3 new markers (DXS1689, DXS1690, and DXS159) and 2 new primer sequences for previously described markers (PGK1P1 and AR). Using two different mapping algorithms based on genotype data alone, we developed two well-supported framework maps containing 15 and 18 markers with average interval sizes of 2.7 and 1.7 cM. The 18 marker map is [DXS426, PFC]-2.0-DXS255-1.2-DXS991-1.6-AR-1.3-DXS153-2.0-DX S106-1.5-DXS132-0.6- DXS1690-0.8-DXS453-1.4-DXS559-1.5-[PGK1, DXS56]-0.6-DXS1002-1.8-DXYS1X-2.0-DXS3-7.5-DX S458-2.8-DXS454, where the distance between adjacent loci is in centimorgans. As a third approach, we used physical mapping data to define bins for markers; this approach permitted us to place 26 markers on our framework map. Finally, we constructed a map based on the physical order of 35 markers from the fifth international workshop on human X chromosome mapping. A comparison of the physical and genetic maps indicates a relationship of 2 cM per megabase in this region, with two regions of reduced recombination. The first is around the centromere (DXZ1), and the second is in the region around PGK1 (DXS441 to DXS995). Our maps should aid in the fine-mapping of the many disease loci that localize to this region of the X chromosome.