Objectives: This study assessed the health costs resulting from the combination of metformin/dipeptidyl peptidase-4 (DPP-4) inhibitors compared with metformin/oral antidiabetes drugs in patients with type 2 diabetes and metabolic syndrome (MS). Patients and Methods: An observational retrospective study was performed. Patients >= 30 years of age who were receiving treatment with metformin who started a second oral antidiabetes therapy in 2008 and 2009 were included. Patients were divided into two groups: (a) metformin plus DPP-4 inhibitors and (b) metformin plus other oral antidiabetes drugs. The main measures were compliance, persistence, metabolic control (glycosylated hemoglobin level of <7%), and complications (hypoglycemia and cardiovascular events). Healthcare and non-healthcare costs were calculated. Patients were followed up for 2 years. An analysis of covariance was carried out (P<0.05 was considered significant). Results: Of the 1,435 patients (mean age, 67.3 years; 53.1% male) who were enrolled, 442 (30.8%) were receiving metformin plus DPP-4 inhibitors, and 993 (69.2%) were receiving metformin plus other oral antidiabetes drugs. The prevalence of MS was 72.2% (95% confidence interval, 71.1-73.3%). Patients treated with DPP-4 inhibitors had better compliance (69.1% vs. 63.8%), persistence (63.8% vs. 53.1%), and metabolic control (69.9% vs. 64.3%) (P<0.01) compared with those receiving other antidiabetes drugs, lower rates of hypoglycemia (14.3% vs. 41.1%) and cardiovascular events (2.9% vs. 5.7%) (P<0.01), and a lower mean adjusted unit cost (euro2,278 vs. euro2,631; P=0.003). Conclusions: Despite the limitations of this observational study, diabetes patients with MS who were treated with metformin plus DPP-4 inhibitors had better compliance, greater metabolic control, and lower rates of hypoglycemia, causing lower costs for the Spanish national health system than patients receiving metformin plus other antidiabetes drugs.