The present study population consists of 2,532 families ascertained through non-syndromic cleft lip with or without cleft palate (CL +/- P) surgical probands born in Denmark between 1941 and 1971. Three samples were derived for analyses of the trait "clefted (CL +/- P) or not." Sample 1 consists of the 26 largest multigenerational families with four or more affected members. Both samples 2-MG and 2-N consist of nuclear families with at least two children and at least one proband among the children. Sample 2-MG contains 846 nuclear families derived from the kindreds with three or more generations. Sample 2-N contains a further 1,181 kindreds with only two generations, nuclear family information available. Four methods of analysis were used: 1) Pedigree analysis was performed on each of the multigenerational kindreds of Sample 1. Results were consistent with autosomal recessive inheritance in eight families and codominant inheritance in three families. These simple genetic hypotheses could not be distinguished in the remaining 15 families. 2) The goodness-of-fit of the multifactorial threshold (MF/T) model was tested in Samples 2-MG and 2-N. The MF/T model was rejected in both samples. 3) Classical segregation analysis was performed on Samples 2-MG and 2-N. Results were consistent with a possible recessive major gene for CL +/- P in Sample 2-MG, but not in Sample 2-N, and with significant admixture of sporadic cases in both samples. 4) Complex segregation analysis under the mixed model was performed on Samples 2-MG and 2-N. In Sample 2-MG, results were consistent with either the general mixed model or with an hypothesis of no major gene. In Sample 2-N, four hypotheses were equally likely: the mixed model with no polygenic component, the mixed model with the major gene component, the mixed model with no sib environmental correlation, and major gene alone. Three conclusions may be drawn: 1) The data provide no support for the MF/T model. 2) The data are consistent with the possibility of a major gene in a portion of the kindreds. 3) The data provide evidence for genetic heterogeneity for CL +/- P.