Abstract Down's syndrome (DS) is a disease with a complex etiology. It is likely that other factors besides genes located on chromosome 21 may play a role in clinical features of affected patients. Tumor necrosis factor-α (TNF-α) (6p21.3) and apolipoprotein E (APOE) (19q13.2) are candidate genes as they interact with the brain deposition of Aβ, one of the neuropathological hallmarks in DS. We examined 136 DS patients and 113 controls for −850 TNF-α and APOE polymorphisms. The −850T frequency in DS was significantly higher than in controls ( P<0.005, OR 2.05, 95% CI 1.22–3.49) while the APOE E4 allele was negatively selected in patients compared to normal subjects ( P<0.005, OR 0.38, 95% CI 0.20–0.71). Our findings suggest that the −850T allele, which is more common among patients at high risk of dementia such as those with DS, might eventually play a role in the development of dementia; no inference on the role of the allele APOE E4 in DS-related dementia may be derived from our results.