We have previously described linkage/association between reelin gene polymorphisms and autistic disorder. APOE also participates in the Reelin signaling pathway, by competitively antagonizing Reelin binding to APOE receptor 2 and to very-low-density lipoprotein receptors. The APOE2 protein variant displays the lowest receptor binding affinity compared with APOE3 and APOE4. In this study, we assess linkage/association between primary autism and APOE alleles in 223 complete trios, from 119 simplex Italian families and 44 simplex and 29 multiplex Caucasian-American families. Statistically significant disequilibrium favors the transmission of epsilon2 alleles to autistic offspring, over epsilon3 and epsilon4 (allele-wise transmission/disequilibrium test [TDT], chi2 = 6.16, 2 degrees of freedom [d.f.], P<0.05; genotype-wise TDT, chi2 = 10.68, 3 d.f., P<0.05). A novel epsilon3r allele was also discovered in an autistic child and his mother. Autistic patients do not differ significantly from unaffected siblings (allele-wise TDT comparing autistic patients versus unaffected sibs, chi2 = 1.83, 2 d.f., P<0.40, not significant). The major limitation of this study consists of our small sample size of trios including one unaffected sibling, currently not possessing the statistical power necessary to conclusively discriminate a specific association of epsilon2 with autism, from a distorted segregation pattern characterized by enhanced epsilon2 transmission rates both to affected and unaffected offspring. Our findings are thus compatible with either (a) pathogenetic contributions by epsilon2 alleles to autism spectrum vulnerability, requiring additional environmental and/or genetic factors to yield an autistic syndrome, and/or (b) a protective effect of epsilon2 alleles against the enhanced risk of miscarriage and infertility previously described among parents of autistic children.