Context: Hormonal treatment in transgender persons affects many components of the metabolic syndrome (MS). Objective: To determine the role of direct hormonal effects, changes in metabolic cytokines, and body composition on metabolic outcomes. Design, Setting, and Participants: 24 transwomen and 45 transmen from the European Network for the Investigation of Gender Incongruence were investigated at baseline and after 12 months of hormonal therapy. Outcome Measures: Best predictors for changes in components of MS, applying least absolute shrinkage and selection operator regression. Results: In transwomen, a decrease in triglyceride levels was best explained by a decrease in fat mass and an increase in fibroblast growth factor 21 (FGF-21); the decrease in total and low-density lipoprotein cholesterol levels was principally due to a decrease in resistin. A decrease in high-density lipoprotein cholesterol depended on an inverse association with fat mass. In contrast, in transmen, an increase in low-density lipoprotein cholesterol was predicted by a decrease in FGF-21 and an increase in the waist/hip ratio; a decrease in the high-density lipoprotein/total cholesterol ratio depended on a decline in adiponectin levels. In transwomen, worsened insulin resistance and increased early insulin response seemed to be due to a direct treatment effect; however, improvements in hepatic insulin sensitivity in transmen were best predicted by a positive association with chemerin, resistin, and FGF-21 and were inversely related to changes in the waist/hip ratio and leptin and adipocyte fatty acid-binding protein levels. Conclusions: The effects of hormonal therapy on different components of the MS are sex-specific and involve a complex interplay of direct hormonal effects, changes in body composition, and metabolic cytokine secretion.