Renal glucose reabsorption was measured with the stepped hyperglycemic clamp in 15 subjects with type 2 diabetes mellitus (T2DM) and 15 without diabetes after 2 days and after more chronic (14 days) treatment with empagliflozin. Patients with T2DM had significantly greater maximal renal glucose transport (TmG) compared with subjects without diabetes at baseline (459 ± 53 vs. 337 ± 25 mg/min; P < 0.05). Empagliflozin treatment for 48 h reduced the TmG in both individuals with and without diabetes by 44 ± 7 and 53 ± 6%, respectively (both P < 0.001). TmG was further reduced by empagliflozin in both groups on day 14 (by 65 ± 5 and 75 ± 3%, respectively). Empagliflozin reduced the plasma glucose concentration threshold for glucose spillage in the urine similarly in individuals with T2DM and without diabetes to <40 mg/dL, which is well below the normal fasting plasma glucose concentration. In summary, sodium-glucose transporter-2 inhibition with empagliflozin reduces both TmG and threshold for glucose spillage in the urine in patients with T2DM and those without diabetes.