Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) encodes a tumor-suppressor phosphatase frequently mutated in both sporadic and heritable forms of human cancer. Germline mutations are associated with a number of heritable cancer syndromes that are jointly referred to as the "PTEN hamartoma tumor syndrome" (PHTS) and include Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome. Germline PTEN mutations have been identified in a significant proportion of patients with PHTS; however, there are still many individuals with classic diagnostic features for whom mutations have yet to be identified. To address this, we took a haplotype-based approach and investigated the association of specific genomic regions of the PTEN locus with PHTS. We found this locus to be characterized by three distinct haplotype blocks 33 kb, 65 kb, and 43 kb in length. Comparisons of the haplotype distributions for all three blocks differed significantly among patients with PHTS and controls (P=.0098, P<.0001, and P<.0001 for blocks 1, 2, and 3, respectively). "Rare" haplotype blocks and extended haplotypes account for two-to-threefold more PHTS chromosomes than control chromosomes. PTEN mutation-negative patients are strongly associated with a haplotype block spanning a region upstream of PTEN and the gene's first intron (P=.0027). Furthermore, allelic combinations contribute to the phenotypic complexity of this syndrome. Taken together, these data suggest that specific haplotypes and rare alleles underlie the disease etiology in these sample populations; constitute low-penetrance, modifying loci; and, specifically in the case of patients with PHTS for whom traditional mutations have yet to be identified, may harbor pathogenic variant(s) that have escaped detection by standard PTEN mutation-scanning methodologies.