Context: The signs and symptoms of Graves' ophthalmopathy (GO) result from inflammation and increased volume of the orbital adipose tissues and extraocular muscles. Objective: To identify differentially regulated genes that may be involved in stimulating the orbital adipose tissue expansion seen in GO. Design: Gene expression profiling was used to compare genes expressed in orbital adipose tissues from GO patients and normal individuals. Setting: Private practice tertiary referral center. Patients: Orbital adipose tissues were collected at transantral orbital decompression surgery from 20 euthyroid patients undergoing this procedure for severe GO and at early autopsy from 8 normal individuals having no evidence of thyroid or ocular disease. Results: Of the 12,686 genes analyzed, 25 known genes were increased in expression (> 4 fold) in GO orbital tissues, while 11 genes were decreased (> 4 fold). Upregulated genes, confirmed by quantitative RT-PCR, included secreted frizzled related protein-1 (sFRP-1; 18.5 fold) and several adipocyte-related genes, including peroxisome proliferator activated receptor- (44.1 fold) and adiponectin (25 fold). Treatment in vitro of GO orbital preadipocytes with recombinant sFRP-1 (100 nM) significantly increased adiponectin (2.0 fold; P < 0.05), leptin (7 fold; P < 0.002), and TSH receptor mRNA (13 fold; P < 0.003) levels, and enhanced Oil red-O staining in the cultures. Conclusions: These results support the concept that orbital adipogenesis is enhanced in GO, and suggest that elevated levels of sFRP-1 in the GO orbit may be involved in stimulating this pathogenic process.