The asymptotic distribution of [MOD] scores under the null hypothesis of no linkage is only known for affected sib pairs and other types of affected relative pairs. We have extended the GENEHUNTER-MODSCORE program to allow for simulations under the null hypothesis of no linkage to determine the empirical significance of MOD-score results in general situations. We performed simulations with families of different size (one million replicates of 500 families per simulation setting) to thoroughly investigate the impact of the pedigree size on the null distribution of multipoint MOD scores. It is shown that the distribution is dependent on the size and structure of the pedigrees under study. By performing simulations in the context of MOD-score analysis, our new tool efficiently explores the linkage data in a comprehensive way and also provides a valid method to inferentially test for linkage. Genet. Epidemiol. 2007. © 2007 Wiley-Liss, Inc.