Context: Polycystic ovary syndrome (PCOS) is a heterogeneous common genetic disorder characterized by hyperandrogenemia and insulin resistance. Alterations in gene expression profiles of the ovary and adipose tissue identified the candidate gene FBJ murine osteosarcoma viral oncogene homolog (FOS) for further investigation of expression changes in metabolic tissues and genetic studies. Objective: The objective of the study was to confirm the underexpression of the FOS gene in sc adipose and determine whether variants in this gene are risk factors for PCOS. Design: RT-PCR was performed in sc fat from women with and without PCOS. Genotyping of single-nucleotide polymorphisms in the FOS locus was performed to test for association with PCOS. Setting: The study was conducted at a tertiary care academic institution. Participants: Twenty-two PCOS and 13 control subjects were recruited for gene expression studies. We assembled a discovery genotyping cohort of 354 cases and 161 controls and a replication cohort of 476 cases and 315 controls, all of whom were Caucasian. Main Measurements: Gene expression by quantitative real-time RT-PCR, FOS genotype, and PCOS status were measured. Results: FOS expression was confirmed to be reduced in PCOS adipose tissue. Three single-nucleotide polymorphisms were significantly associated with PCOS in the discovery cohort (rs8006998, P = 0.0031; rs8013918, P = 0.0006; rs8013942, P = 0.0087). rs8006998 was also associated with PCOS in the replication cohort (P = 0.013). Conclusions: Differential gene expressionin sc fat and genetic association at the FOS locus in PCOS subjects implicates a role for this transcription factor in PCOS. FOS dysfunction may be a common factor between hyperandrogenism and insulin resistance. Copyright © 2012 by The Endocrine Society.