Nonspecific X-linked mental retardation (XLMR) is a common disorder. The number of genes involved in this condition is not known, but it is estimated to be more than 10. We present a clinical and linkage study on 3 families with XLMR. All families were analyzed using highly polymorphic markers covering the X chromosome; screening for the fragile X mutation was negative. The first family (MRX 36) consisted of 1 female and 4 male patients in 3 generations and 7 healthy individuals. Considering the female as an expressing heterozygous carrier, a maximum LOD score of 3.41 was reached in region Xp21.2-Xp22.1. Considering her phenotype to be unknown, a LODmax of 1.97 was reached in the same region. The second family consisted of 5 affected and 6 healthy males with mild to borderline mental retardation. Linkage analysis using an X-linked recessive model with full penetrance and no phenocopies excluded linkage over almost the entire X chromosome. Using alternative models, including an affecteds-only analysis, a LODmax of 1.49 was found in region Xq24-28. The third family, consisting of 4 male patients with moderate mental retardation in 1 generation yielded a LODmax of 0.9 in region Xp22.13-11.3. However, even in this small pedigree, exclusion mapping was able to exclude very large parts of the X chromosome and in this way identify a likely candidate region.