OBJECTIVE: The literature lacks data on the use of the gold-standard hyperinsulinemic-euglycemic clamp (HEC) technique for the evaluation of insulin resistance (IR) in depot-medroxyprogesterone acetate (DMPA) users. This study assessed carbohydrate metabolism in non-obese users of DMPA using the HEC technique. STUDY DESIGN: A prospective, non-randomized, comparative study conducted at the Family Planning Clinic/Metabolic Unit, University of Campinas, Brazil. Forty-eight women aged 18-39 years underwent HEC: 30 initiating use of DMPA and 18 initiating use of a copper intrauterine device (IUD). Data from 15 women in each group, who completed the follow-up and underwent HEC at12 months, were compared using repeated measures ANOVA. All women were advised to perform aerobic physical exercise for 150 min/week; body composition and total energy intake were evaluated. Main outcome measures were IR defined by M-value <4 mg/kg/min, and blood levels of insulin. Additional outcomes were total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, adipokines and free fatty acids. RESULTS: At 12 months, two women in the DMPA group and none in the IUD group had developed IR. The groups were similar in in M-values and in blood levels of insulin, total cholesterol, HDL-cholesterol, LDL-cholesterol, adipokines or free fatty acids. Triglyceride levels increased in the DMPA group when compared to the IUD group, 80.0 (SD 47.8) versus 61.8 (SD 35.8) mg/dL respectively, (p=.033); and increased the total daily energy intake, 1828.3 (SD 518.9) versus 1300.8 (SD 403.4) kilocalories/24hs, respectively in the same groups, (p=.041). All the DMPA users showing higher insulin sensitivity at 12 months reported performing physical activity regularly. CONCLUSIONS: Changes occurred in carbohydrate metabolism in DMPA users in the first year of use of the method. It is possible that the regular aerobic exercise may exert a beneficial and protective effect against the factors that trigger these changes. IMPLICATIONS STATEMENT: Carbohydrate metabolism undergoes adverse changes in few young non-obese women during the first year of DMPA use and regular aerobic exercise may exert a beneficial and protective effect against these changes.