Aim:  To compare the efficacy and safety of sitagliptin vs. glipizide in patients with type 2 diabetes and inadequate glycaemic control haemoglobin A1c (HbA1c) ≥ 6.5 and ≤10% on metformin monotherapy. Methods:  After a metformin dose titration/stabilization period (≥1500 mg/day), 1172 patients were randomized to the addition of sitagliptin 100 mg q.d. (N = 588) or glipizide 5 mg/day (uptitrated to a potential maximum 20 mg/day) (N = 584) for 52 weeks. The primary analysis assessed whether sitagliptin was non‐inferior to glipizide regarding HbA1c changes from baseline at Week 52 using a per‐protocol approach. Results:  From a mean baseline of 7.5%, HbA1c changes from baseline were −0.67% at Week 52 in both groups, confirming non‐inferiority. The proportions achieving an HbA1c < 7% were 63% (sitagliptin) and 59% (glipizide). Fasting plasma glucose changes from baseline were −0.56 mmol/l (−10.0 mg/dl) and −0.42 mmol/l (−7.5 mg/dl) for sitagliptin and glipizide, respectively. The proportion of patients experiencing hypoglycaemia episodes was significantly (p < 0.001) higher with glipizide (32%) than with sitagliptin (5%), with 657 events in glipizide‐treated patients compared with 50 events in sitagliptin‐treated patients. Sitagliptin led to weight loss (change from baseline =−1.5 kg) compared with weight gain (+1.1 kg) with glipizide between‐treatment difference (95% confidence interval) =−2.5 kg (−3.1, −2.0); p < 0.001. Conclusions:  In this study, the addition of sitagliptin compared with glipizide provided similar HbA1c‐lowering efficacy over 52 weeks in patients on ongoing metformin therapy. Sitagliptin was generally well tolerated, with a lower risk of hypoglycaemia relative to glipizide and with weight loss compared with weight gain with glipizide.