The concentration of circulating homocysteine has been associated with a variety of diseases, including myocardial infarction, stroke, venous thrombosis and cognitive decline. Genetic variation has been demonstrated to play an important role in determining plasma homocysteine, however, the genes involved are incompletely understood. Ligation of the transcription factor peroxisome proliferator-activated gamma (PPARG) has been demonstrated to lower plasma homocysteine. We examined the association of two sequence variations in PPARG with plasma concentrations of homocysteine in a population-based study of 3,875 elderly men. PPARG c.34G > C and PPARG c.1347C > T sequence variations were determined by real-time quantitative PCR and related to logarithm transformed homocysteine concentrations using linear regression, adjusting for the co-variants age, renal function, smoking, coronary heart disease, waist to hip ratio, diabetes, hypertension and MTHFR g.677C > T sequence variation. Median plasma homocysteine concentration was 10% higher in men who were homozygous for the rare allelic variation in PPARG c.34G > C and PPARG c.1347C > T by comparison to those who had wild type sequence variation. PPARG c.1347C > T (beta = 0.038, P = 0.01 recessive model; beta = 0.036, P = 0.02 dominant model) sequence variation was positively associated with homocysteine concentration after adjusting for co-variants. The two PPARG sequence variations were in linkage disequilibrium and the common haplotype was associated with lower plasma homocysteine (P = 0.005). Our findings demonstrate a new genotypic association with plasma homocysteine. Replication will be required in other cohorts.