The contemporary urban mixed Chilean population stems from the admixture of the native Amerindians with the Spaniards, showing an average incidence rate of nonsyndromic cleft lip with or without cleft palate (NSCLP) of 1.8 per 1000 live births. Complex segregation analysis using the computer program POINTER was conducted in two hundred and forty-nine (249) extended pedigrees distributed in 202 simplex families and 47 multiplex families ascertained from affected NSCLP probands (157 males and 92 females). These pedigrees yielded 326 affected individuals and over 1454 family members. Eight hypothetical models were examined and compared by -2 log-likelihood ratio χ2 test. Models postulating that NSCLP was not transmitted in these families were rejected as well as model postulating only a multifactorial component (P < 0.0001). Model postulating no polygenic component to transmission could not be rejected but the model of no transmission of the major effect was rejected (P < 0.0001). Among the major locus models only the recessive model of transmission was rejected whereas codominant and dominant inheritance without a multifactorial component could not be excluded. The unrestricted model suggests that the frequency of the NSCLP susceptibility allele at the major locus is 0.0037, and its penetrance is 92%.