Fanconi anemia (FA) is characterized clinically by a progressive pancytopenia, diverse congenital abnormalities and increased predisposition to malignancy. Although a variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in some patients, study of cellular sensitivity to the clastogenic effect of DNA cross-linking agents such as diepoxybutane (DEB) has been used to facilitate the diagnosis. Data from DEB-induced chromosomal breakage studies of 328 peripheral blood specimens from patients considered at risk for FA were analyzed using a stepwise multivariate logistic regression, in order to determine which method of representing the data best discriminated between DEB-sensitive (DEB+) and DEB-insensitive (DEB-) cases. Similar methods were applied to the data from the International Fanconi Anemia Registry (IFAR) to determine whether DEB+ and DEB- cases may be considered as distinct clinical entities, and if so, which variables provide the best discrimination between the two groups. We conclude that hypersensitivity to the clastogenic effect of DEB is a useful discriminator for FA. A simplified scoring method for classifying patients on the basis of eight clinical manifestations that are the best predictors for FA is presented. Our data indicate that the clinical diversity in FA is more widespread than previously recognized.