Context & Aim: Low-dose pioglitazone (Pio), flutamide (Flu), metformin (Met) plus an estro-progestagen is a novel polytherapy lowering total and visceral adiposity and reducing carotid intima media thickness (IMT) in hyperinsulinaemic women with androgen excess, without changing their body mass index (BMI). In a search for mediators of PioFluMet's actions, we measured serum levels of visfatin and high-molecular-weight (HMW) adiponectin. Design & Patients: In a double-blind study, we enrolled 38 young women with hyperinsulinaemic androgen excess [mean BMI 23.7 Kg/m(2)], all of whom started on Flu (62.5 mg/d), Met (850 mg/d) and a transdermal estro-progestagen, each for 21/28 d over 1 yr. Patients were randomly assigned to receive, in addition, placebo (n=19) or Pio (7.5 mg/d; n=19) on the same 21/28 d. Measurements: Serum concentrations of visfatin and HMW adiponectin; visceral fat by magnetic resonance imaging; carotid IMT by ultrasound, all at study start and after 1 yr. Results: PioFluMet raised visfatin by a mean 84% and HMW adiponectin by 157% (P<0.001), and reduced visceral fat and IMT by a mean 22% and 31% (both P<0.001). Low-dose Pio accounted for about half of the PioFluMet effects on IMT, visfatin and HMW adiponectin. Conclusion: In hyperinsulinaemic women with androgen excess, low-dose polytherapy with PioFluMet evoked striking rises in both circulating visfatin and HMW adiponectin, while lowering IMT and reducing visceral adiposity within 1 yr.