Podoconiosis (endemic non-filarial elephantiasis) is a geochemical disease occurring in individuals exposed to red clay soil derived from alkalic volcanic rock. It is a chronic, debilitating disorder and a considerable public health problem in at least 10 countries in tropical Africa, Central America and northern India. Only a small proportion of individuals exposed to red clay develop disease and familial clustering of cases occurs, so we tested the hypothesis that disease occurs in genetically susceptible individuals on exposure to an environmental element in soil. Using multiple statistical genetic techniques we estimated sibling recurrence risk ratio (lambda(s)) and heritability for podoconiosis, and conducted segregation analysis on 59 multigenerational affected families from Wolaitta Zone, southern Ethiopia. We estimated the lambda(s) to be 5.07. The heritability of podoconiosis was estimated to be 0.629 (SE 0.069, P=1x10(-7)). Segregation analysis showed that the most parsimonious model was that of an autosomal co-dominant major gene. Age and use of footwear were significant covariates in the final model. Host genetic factors are important determinants of susceptibility to podoconiosis. Identification of the gene(s) involved will lead to better understanding of the gene-environment interactions involved in the pathogenesis of podoconiosis and other complex multifactorial conditions.