To assess the genetic contribution to proliferative vitreoretinopathy (PVR) and report the strong association observed in the tumor necrosis factor (TNF) locus. As a component of The Retina 4 Project, a case-controlled, candidate gene association study in the TNF locus was conducted. Blood from 450 patients with (138 cases) and without (312 controls) post-rhegmatogenous retinal detachment (RD) PVR was genotyped to determine polymorphisms located in the TNFα gene. Single nucleotide polymorphisms (SNPs) with correlation coefficients of ≥ 0.8 and a minor allelic frequency of ≥ 10% were studied. Functional SNPs or SNPs previously described in association with other inflammatory diseases were also added for analysis. The SNPlex Genotyping System (Applied Biosystems, Foster City, CA) was used for genotyping. Single nucleotide polymorphism and haplotype analyses were performed. Bioinformatic tools were used to evaluate those SNPs that were significantly associated. Single and haplotypic significant associations with PVR. A total of 11 common tag SNPs in the following genes were analyzed: lymphotoxin alpha (LTA), TNFα, leukocyte-specific transcript 1 (LST1), and the activating natural killer receptor p30 (NCR3). After permutation, there was a significant association in the non-synonymous polymorphism rs2229094(T→C) in the LTA gene (P = 0.0283), which encodes a cysteine to arginine change in the signal peptide. This marker was also present in all significant haplotypic associations and was not observed in any nonsignificant associations. When this SNP was analyzed using bioinformatic tools, the hydropathy profile changed, as well as the transmembrane region and the splicing site predictions. The strong association found in the rs2229094(T→C) of the LTA gene may indicate an important role of this polymorphism in the development of PVR. If supported in extended studies, the rs2229094(T→C) may have significant implications regarding the genetic risk of the retinal repairing process. Copyright © 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.