Objectives: We investigated the efficacy of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes for 4 years in clinical practice. Methods: Between 2009 and 2010, we reviewed 1,178 patients with type 2 diabetes (HbA1c≥7.5% or 58 mmol/mol) prescribed initial combination therapy with sitagliptin and metformin. After excluding 288 patients without a second follow-up, 890 individuals (age, 58.0 ± 12.5 years; BMI, 25.4 ± 3.5 kg/m2; HbA1c, 8.6 ± 1.1%) were followed up with every 3-6 months for 4 years. Homeostasis model assessments for insulin resistance and β-cell function (HOMA-β) were recorded at baseline. The response criterion was HbA1c reduction by ≥0.8% from baseline or attainment of the target HbA1c (≤7.0% or 53 mmol/mol). At the end of every year of treatment, changes in HbA1c from the baseline were assessed. Results: After 1 year, 72.2% of patients with initial combination therapy had responded, defined as HbA1c reduction ≥0.8% or attainment of the target HbA1c≤7.0%. After 4 years, 35.4% of the patients still showed a response, with an HbA1c level of 7.0 ± 0.9%. A high HbA1c level at baseline was the most significant independent predictor of the long-term response (P<0.001). In addition, low HOMA-β was a significant predictor of a greater reduction in HbA1c. This treatment was generally well tolerated over the 4-year follow-up period, without any serious adverse events. Conclusions: This real-world follow-up study shows a persistent glucose-reducing effect of initial combination therapy with sitagliptin and metformin for up to 4 years.