OBJECTIVE: The PPAR gamma transcription factor, is involved in both adipogenesis and inflammation, which have been implicated in the pathogenesis of thyroid-associated orbitopathy (TAO). The aim of this study was to explore the possibility that the Pro(12)Ala polymorphism of the PPAR gamma gene, associated with a modified transcriptional activity, might be affecting the severity of TAO. SUBJECTS AND DESIGN: We studied two cohorts of patients with Graves' disease (GD): Group 1 comprised 172 patients of Dutch ethnic origin with TAO, who attended the outpatients' clinic, Department of Endocrinology and Orbital Centre of the Academic Medical Centre, Amsterdam. Group 2 comprised 93 consecutive patients with GD of Greek ethnic origin, who did not have TAO. In group 1, exophthalmometry measurements, lid oedema, diplopia (n = 172) and clinical activity score (CAS) (n = 110), always assessed by the same group of three investigators, were recorded. Autoantibody levels were measured. RESULTS: Allele frequency was 11.5%. There was no difference in the distribution of the polymorphism between GD patients with and without TAO. Among group 1 patients proptosis was significantly lower in Pro(12)Ala carriers (20.1 +/- 3.3 vs. 22.1 +/- 3.1, P = 0.003, t-test). PPAR gamma polymorphism carriers had lower TSH-Rab levels (mean rank 61.8 vs. 83.2, P = 0.015) and lower CAS (available in 110 patients) (mean rank 38.9 vs. 55.4, P = 0.022, M-W-test). The frequency of the polymorphism decreased with increasing CAS (P = 0.023 linear by linear association). Multivariate analysis (step) showed that the association of either proptosis or CAS with the PPAR gamma gene variant remained significant when age, smoking and TSH-Rab levels were taken into account (P < 0.01). CONCLUSIONS: The distribution of the Pro(12)Ala PPAR gamma gene polymorphism is equally present in patients with GD with or without TAO. Among patients with TAO this polymorphism is associated with less-severe and less-active disease.