To investigate the impact of peroxisome proliferator-activated receptor α (PPAR α) SNPs and gene-obesity interaction on diabetic retinopathy (DR) susceptibility in a Chinese Han population. A total of 812 patients (373men, 439 women) with type 2 diabetes mellitus (T2DM), with a mean age of 53.3±14.0 years old, were selected, including 402 diabetic retinopathy patients and 410 controls. Three single nucleotide polymorphisms (SNPs) were selected for genotyping in the case-control study: rs4253778, rs135539 and rs1800206. Generalised multifactor dimensionality reduction (GMDR) and logistic regression model was used to examine the association and interaction between SNP and obesity on DR, odds ratio (OR) and 95% confident interval (95%CI) were calculated. The carriers of homozygous mutant of rs1800206 SNP revealed decreased DR risk than those with wild-type homozygotes, OR (95%CI) was 0.78 (0.66-0.94). GMDR analysis indicated a significant two-locus model (p=0.0107) involving rs1800206 and abdominal obesity, indicating a potential interaction among rs1800206 and abdominal obesity. Overall, the two-locus models had a cross-validation consistency of 10 of 10, and had the testing accuracy of 60.72%. We also found that subjects with abdominal obesity and LV or VV genotype have lowest DR risk, compared to subjects with normal WC and LL genotype, OR (95%CI) was 0.39 (0.30-0.74), after covariates adjustment. Our results support an important association between rs1800206 minor allele of PPAR α and DR, and the interaction analysis also shown a combined effect of Leu162 allele-abdominal obesity interaction on DR. Copyright © 2015 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.