The tricho-dento-osseous (TDO) syndrome demonstrates kinky curly hair, thin-pitted enamel, taurodontism, and thickening of cortical bone. The purpose of this investigation was to characterize the phenotypic variation of TDO in 3, previously unreported, kindreds and to examine possible candidates for the genomic TDO locus. Thirty-three affected and 20 unaffected individuals were recruited for prospective analysis. Participants were evaluated clinically and photographed by one examiner. Blood was drawn for genetic linkage analyses and radiographs were taken to assess dental and skeletal characteristics. All TDO individuals with teeth had generalized thin and/or pitted enamel hypoplasia. Taurodontism was present in all affected individuals, but was variably expressed. Unique kinky/curly hair at birth was reported in 85% of affected individuals. The curly hair phenotype was retained in 46% of affected individuals after infancy. Thick cranial bones, lack of visible pneumatization of the mastoid process, and/or obliteration of the calvarial diploë was seen in 97% of affected persons compared with 30% of the unaffected individuals. The findings suggest that curly hair at birth, enamel hypoplasia, and taurodontism are highly penetrant yet clinically variable components of TDO. The ABO, Kell, and Gc loci previously suggested to be linked to TDO were excluded as candidates in this TDO population. This investigation characterizes the marked variability in the expression of skeletal, hair, and dental manifestations. The broad range of TDO phenotypes seen in these families, including a variety of skeletal changes, does not support subdividing TDO into multiple subtypes based on subtle phenotypic differences. Am. J. Med. Genet. 72:197–204, 1997. © 1997 Wiley-Liss, Inc.