Serrated polyposis (SPP) is characterized by the development of multiple serrated polyps and an increased predisposition to colorectal cancer (CRC). In the present study, we aimed to characterize, at a clinical and molecular level, a cohort of SPP patients with or without a family history of SPP and/or polyps/CRC (SPP-FHP/CRC). Sixty-two lesions from 12 patients with SPP-FHP/CRC and 6 patients with sporadic SPP were included. The patients with SPP-FHP/CRC presented with an older mean age at diagnosis (p=0.027) and a more heterogeneous histological pattern of lesions (p=0.032) than the patients with sporadic SPP. We identified two molecular forms of SPP-FHP/CRC, according to the preferential location of the lesions: proximal/whole-colon or distal colon. Mismatch repair (MMR) gene methylation [mutS homolog 6 (MSH6)/mutS homolog 3 (MSH3)] or loss of heterozygosity (LOH) of D2S123 (flanking MSH6) were detected exclusively in the former (p=3.0x10-7), in most early lesions. Proximal/whole‑colon SPP-FHP/CRC presented a higher frequency of O-6-methylguanine-DNA methyltransferase (MGMT) methylation/LOH, microsatellite instability (MSI) and Wnt mutations (19/29 vs. 7/17; 16/23 vs. 1/14, p=2.2x10-4; 15/26 vs. 2/15, p=0.006; 14/26 vs. 4/20, p=0.02) but a lower frequency of B-raf proto-oncogene, serine/threonine kinase (BRAF) mutations (7/30 vs. 12/20, p=0.0089) than the distal form. CRC was more frequent in cases of Kirsten rat sarcoma viral oncogene homolog (KRAS)-associated proximal/whole-colon SPP-FHP/CRC than in the remaining cases (4/4 vs. 1/8, p=0.01). Thus, SPP-FHP/CRC appears to be a specific entity, presenting two forms, proximal/whole-colon and distal, which differ in the underlying tumor initiation pathways. Early MGMT and MMR gene deficiency in the former may underlie an inherited susceptibility to genotoxic stress.