The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-inducible transcription factor that suppresses microglial inflammatory responses and inhibits amyloid beta (Aβ) production through promoting cholesterol efflux from glial cells. PPAR-γ agonists have been advanced as a new disease altering approach to Alzheimer's disease (AD), with rosiglitazone therapy having improved cognition in those AD patients that did not possess an Apolipoprotein E (APOE) ε4 allele. The current study was designed to explore the effect of interactions between PPAR-γ and APOE gene polymorphisms on the AD risk. We examined genetic variations of PPAR-γ by genotyping 7 haplotype tagging SNPs (htSNPs) (rs10510412, rs17793951, rs1801282, rs4135263, rs1151999, rs709149, and rs709154) in a group of 352 Spanish late-onset AD cases and 438 controls. The PPAR-γ TCCA haplotype derived from SNPs in introns 4 (rs4135263), 5 (rs1151999), and 6 (rs709149 and rs709154) showed a strong protective effect against AD in APOE ε4 allele noncarriers (p=0.001, permutation p=0.006, Bonferroni corrected p=0.021), with a frequency of 39% in cases and 50% in controls. Our data suggest that PPAR-γ genetic variants may modify the risk of AD in an APOE ε4 allele-dependent fashion.