Clinical biomarkers can predict normalization of HbA1c after Roux-en-Y gastric bypass (RYGB) surgery, but it is unclear which are the most predictive.The aim of this study was to compare biomarkers for insulin sensitivity and other clinical parameters in the prediction of normalization of HbA1c after RYGB surgery. This study included 99 (23 men) obese subjects (BMI > 35 kg/m2) undergoing a laparoscopic RYGB. Clinical and biochemical examinations were performed pre-operatively and up to 2 years after surgery. Pre-operatively, normal fasting glucose levels were found in 25 individuals (NG), prediabetes in 46 and type 2 diabetes (T2DM) in 28. At baseline IGF-I (SD), IGFBP-1 and adiponectin levels were low while leptin was high. Weight loss was observed in all three groups, most in the prediabetes group. After 2 years HbA1c was decreased in prediabetes and T2DM. In all three groups insulin, HOMA-IR, lipids and blood pressure improved, IGFBP-1 and adiponectin increased and leptin decreased. IGF-I (SD) increased only in T2DM. In those with prediabetes or T2DM (n = 74), HbA1c at 2 years correlated to baseline BMI (r = -0.27, p = 0.028), age (r = 0.43, p < 0.001), HbA1c (r = 0.37, p = 0.001) and IGFBP-1 (r = 0.25, p = 0.038), and was normalized in 45/74 (61%) at 1 year and in 36 subjects (49%) at 2 years. These responders were younger, had higher BMI, larger waist circumference, lower HbA1c and lower IGFBP-1 levels at baseline. In a multiple regression model age (negative, p = 0.021) and waist circumference (positive, p = 0.047) were the only predictors for normalized HbA1c. RYGB normalized HbA1c in 49% at two years follow-up, which was predicted by low baseline IGFBP-1 level, a marker of hepatic insulin sensitivty and insulin secretion. However,. younger age and larger waist circumference were the only predictors of normalized HbA1c in multivariate analysis.