We prospectively assessed whether metabolic and menstrual benefits of metformin-diet were equally realized in women with polycystic ovary syndrome (PCOS), categorized by pretreatment top (n = 32) and bottom (n = 35) quintile homeostasis model assessment insulin resistance (IR). Effects of metformin (2.55 g/d) and diet (6300-8400 J/d [1500-2000 cal/d], 26% protein, 44% carbohydrate) were prospectively assessed for 12 months. Pretreatment, the bottom and top insulin-resistant quintile groups differed by median weight (84 vs 121 kg), insulin (7.8 vs 40.5 I(1/4) U/mL), IR (1.62 vs 9.28), homeostasis model assessment insulin secretion (131 vs 416), glucose (82 vs 98 mg/dL), sex hormone-binding globulin (40 vs 15 nmol/L), (all P < .0001), free androgen index (2.76 vs 10.8) ( P < .001), triglyceride (92 vs 131 mg/dL), high-density lipoprotein (46 vs 39 mg/dL), systolic blood pressure (116 vs 128 mm Hg), and diastolic blood pressure (76 vs 84 mm Hg), (all P < .01). After 12 months on metformin-diet, weight fell by 7% in both insulin-resistant groups (P < .0001), insulin, IR, and insulin secretion fell in the top insulin-resistant group by 60%, 64%, and 39% (all P < .0001), with smaller reductions in the bottom insulin-resistant group of 18%, 13% (P > .05 for both), and 22% (P < .01), respectively. The free androgen index fell 39% (P > .01) in the top insulin-resistant group. The pretreatment percentage of expected menses in the top insulin-resistant quintile (26 +/- 39%) was 1.6 times less than in the bottom insulin-resistant quintile (41 +/- 38%) (P = .026). Over the 12-month treatment period, the percentage of spontaneous regular normal menses increased to 72 +/- 27% in the top insulin-resistant quintile group (P < .0001) and to 77 +/- 31% in the bottom quintile group (P < .0001), with no group difference (P = .33). Metformin-diet metabolic effects were much more marked in women in the top vs the bottom quintile for IR. Women with PCOS in the bottom insulin-resistant quintile, conventionally thought not to respond optimally to metformin-diet, nevertheless experience significant metabolic and menstrual benefits. Metformin-diet should benefit most women with PCOS, even those with normal serum insulin, without IR.