OBJECTIVE - Insulin resistance has been reported in up to 70% of women with polycystic ovary syndrome (PCOS). Physiologic and genetic data currently implicate post-insulin receptor signaling defects in substrates such as glycogen synthase kinase 3(3 (GSK3(3). The AKT2 gene was chosen as a candidate for PCOS because its product affects glucose metabolism and mitogenic signaling, interacts with GSK3(, and mediates cell survival in the ovary. RESEARCH DESIGN AND METHODS - Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham, and control subjects were recruited from the surrounding community; 287 white women with PCOS and 187 white control subjects were genotyped for four single nucleotide polymorphisms (SNPs) in AKT2. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles. SNPs and haplotypes were tested for association with PCOS risk and phenotypic markers of PCOS. RESULTS - Minor allele carriers of SNPs rs3730051 and rs8100018 had increased odds of PCOS (odds ratio [OR] 2.2, P = 0.004, and 2.4, P = 0.001, respectively). The haplotype T-G-C-T was significantly associated with PCOS (OR 2.0, P = 0.01). Carriers of the risk haplotypes for both AKT2 and GSK3B had a further increased odds of PCOS (OR 3.1, P = 0.005). CONCLUSIONS - These data suggest that polymorphisms in two components of the insulin signaling pathway, AKT2 and GSK3B, are associated with PCOS. The presence of multiple lesions in a single pathway may confer increased risk. © 2008 by the American Diabetes Association.