Background Thiazolidinediones (TZDs) have been associated with various safety concerns including weight gain, bladder cancer, and congestive heart failure (CHF). This study evaluated the efficacy and safety of lobeglitazone, a novel TZD in patients with type 2 diabetes mellitus (T2DM) in real practice. Methods In this non-interventional, multi-center, retrospective, and observational study conducted at 15 tertiary or secondary referral hospitals in Korea, a total of 2,228 patients with T2DM who received lobeglitazone 0.5 mg for more than 1 year were enrolled. Results Overall adverse events (AEs) occurred in 381 patients (17.10%) including edema in 1.97% ( n =44). Cerebrovascular and cardiovascular diseases were identified in 0.81% ( n =18) and 0.81% ( n =18), respectively. One case of CHF was reported as an AE. Edema occurred in 1.97% ( n =44) of patients. Hypoglycemia occurred in 2.47% ( n =55) of patients. Fracture occurred in 1.17% ( n =26) of all patients. Lobeglitazone significantly decreased HbA1c level, resulting in a mean treatment difference of −1.05%± 1.35% ( P <0.001), and decreased total cholesterol, triglyceride, and low-density lipoprotein cholesterol. However, it increased high-density lipoprotein cholesterol, regardless of statin administration. The patients who received lobeglitazone 0.5 mg showed an apparent reduction in glycosylated hemoglobin (HbA1c) from baseline during the first 6 months of treatment. The HbA1c levels remained stable between months 6 and 42. Conclusion Lobeglitazone has long-term safety profile, good glycemic-lowering effect and long-term durability of glycemic control in real-world clinical settings.