Autozygosity mapping has been invaluable for determining the genetic basis of lethal autosomal recessive disorders, but this approach remains challenging because DNA from affected individuals may often be unavailable or of insufficient quality for extensive molecular genetic studies. To circumvent these difficulties, we developed a computer program called "SAMPLE" (for shadow autozygosity mapping by linkage exclusion) to enhance autozygosity mapping through the empirical analysis of haplotypes of unaffected individuals in consanguineous families. Single nucleotide polymorphism (SNP) genotyping of unaffected individuals in complex consanguineous pedigrees is used to infer limited chromosomal regions compatible with linkage to a potential disease locus, and to allow the immediate prioritization of potential regions of interest. Further limited genotyping then enables the rapid confirmation and fine mapping of a disease locus. We demonstrate the utility of this strategy by using genotyping data from only parents and unaffected siblings, in three consanguineous families affected with Meckel-Gruber syndrome, to correctly infer the location of the MKS3/TMEM67 locus on chromosome 8q22.1. This strategy is practicable only with the recent advances in whole genome genotyping by high-density SNP microarrays, and could not be easily implemented in approaches that rely on microsatellite markers. SAMPLE is available at http://dna.leeds.ac.uk/sample/.