Taking advantage of increasingly available high-density single nucleotide polymorphisms (SNP) markers across the genome, various types of transmission/disequilibrium tests (TDT) using haplotype information have been developed. A practical challenge arising in such studies is the possibility that transmitted haplotypes have inherited disease-causing mutations from different ancestral chromosomes, or do not bear any disease-causing mutations (founder heterogeneity). To reduce the loss of signal strength due to founder heterogeneity, we propose an SP-TDT test that combines a sequential peeling procedure with the haplotype similarity based TDT method. The proposed SP-TDT method is applicable to any size of nuclear family with or without ambiguous phase information. Simulation studies suggest that the SP-TDT method has the correct type I error rate in stratified populations, and enhanced power compared with some existing haplotype similarity based TDT methods. Finally, we apply the proposed method to study the association of the leptin gene with obesity from the National Heart, Lung, and Blood Institute Family Heart Study. © University College London 2005.