Polycystic ovary syndrome (PCOS) affects 10% of women and is associated with an increased risk of type 2 diabetes and fatty liver disease. Androgen excess is an important driver of metabolic risk in PCOS. In adipose tissue from women with PCOS, increased activation of androstenedione (A4) to testosterone (T) by the enzyme AKR1C3 results in systemic lipotoxicity. Recent in-vitro studies also demonstrated that T and 11-ketotestosterone (11KT) activate the androgen receptor with similar potency and that AKR1C3 activates 11-ketoandrostenedione (11KA4) to 11KT with higher efficiency than A4 to T. Furthermore, 11-oxygenated androgens including 11KT constitute the majority of circulating androgens in PCOS. Here, we examined intra-adipose activation of classic and 11-oxygenated androgens and their differential metabolic impact. We performed ex-vivo primary adipose tissue incubations of paired subcutaneous (sc) and omental (om) samples obtained from eight women undergoing bariatric surgery (age 3259 years; BMI 4457 kg/m2). Incubations with A4 and 11KA4, respectively, revealed significantly higher AKR1C3-mediated conversion of 11KA4 to 11KT than conversion of A4 to T. Untargeted metabolome analysis by mass spectrometry revealed differential adipose tissue metabolic responses, with predominant alterations of glycerophospholipid metabolism in sc adipose, which were more pronounced in response to 11-oxygenated than classic androgens. Co-incubation of adipose explants with 11KA4 and a selective HSD11B1 inhibitor significantly enhanced the activation of 11KA4 to 11KT by decreasing the HSD11B1-catalysed inactivation of 11KA4 to 11β-hydroxyandrostenedione. Urinary steroid profiling by gas chromatography-mass spectrometry in 8 women (age 2335, BMI 2549) treated for 12-weeks with a HSD11B1 inhibitor demonstrated the expected reduction in glucocorticoid activation, but also a significant shift in the ratio of urinary 11-oxygenated androgen metabolites towards the active keto-derivatives, reflective of increased activation of 11-oxygenated androgens. We conclude that local activation of 11-oxygenated androgens is the predominant source of androgen exposure in adipose tissue and enhances systemic lipotoxicity.