ABSTRACT Objective Polycystic ovary syndrome (PCOS) is an endocrine disease characterized by metabolic, reproductive, and psychological manifestations. Growth and differentiation factor 15 (GDF-15) is a cytokine associated with metabolic and inflammatory disorders. Metformin is commonly used for the treatment of PCOS. We investigated the relationship between GDF-15 levels and PCOS, the effect of metformin on GDF-15 levels, and potential biologic pathways related to GDF-15. Subjects and methods The study included 35 women with PCOS and 32 women without PCOS (controls). Both groups were compared in terms of GDF-15 levels. Additional analysis was conducted on samples from 22 women with PCOS who were treated with either metformin (n = 7) or placebo (n = 15), retrieved from a previous randomized, controlled trial. Levels of GDF-15 were measured using MILLIPLEX. The biologic pathways related to GDF-15 were evaluated using the databases STRING, SIGNOR, and Pathway Commons. The statistical analysis was conducted using the software SPSS. Results Levels of GDF-15 were higher in the PCOS group compared with the non-PCOS group (p = 0.039). Among women with PCOS, GDF-15 levels were higher in those treated with metformin compared with placebo (p = 0.007). The proteins related to GDF-15 overlapped between the databases, and a significant interaction was found between GDF-15 and proteins related to PCOS and its complications, including those related to estrogen response, oxidative stress, ovarian infertility, interleukin (IL)-18, IL-4, the ratio of advanced glycation end products to their receptor (AGE/RAGE), leptin, transforming growth factor beta (TGF-β), adipogenesis, and insulin. Conclusion The findings of the present study suggest a relationship between GDF-15 and PCOS and a potential increase in GDF-15 levels with metformin treatment. An additional finding was that GDF-15 could be involved in biologic pathways related to PCOS complications. (PCOS reproductive manifestations 1 GDF15 GDF (GDF-15 disorders GDF-1 GDF15. 15. 3 controls. controls . (controls) 2 n 7 15, , 15) randomized trial MILLIPLEX STRING SIGNOR Commons SPSS nonPCOS non p 0.039. 0039 0.039 0 039 0.039) 0.007. 0007 0.007 007 0.007) complications response stress infertility IL18, IL18 IL 18, 18 (IL)-18 IL4, IL4 4, 4 IL-4 AGE/RAGE, AGERAGE AGE/RAGE AGE RAGE (AGE/RAGE) leptin TGFβ, TGFβ TGF β (TGF-β) adipogenesis insulin GDF1 (GDF-1 GDF- (controls 003 0.03 03 000 0.00 00 IL1 (IL)-1 IL- (AGE/RAGE (TGF-β (GDF- 0.0 (IL)- (GDF 0. (IL) (IL