INTRODUCTION: J-DISCOVER aims to research the treatment reality of Japanese patients with type 2 diabetes mellitus who begin second-line treatment. Here we report baseline characteristics and factors associated with selection of second-line treatment. METHODS: J-DISCOVER is a prospective, observational, multicenter, cohort study in patients with type 2 diabetes (aged ≥ 20 years) beginning second-line treatment after first-line oral monotherapy. Baseline characteristics and treatment patterns were descriptively summarized. Logistic regression models were used to identify factors associated with specific second-line treatments. RESULTS: A total of 1806 patients (mean age 61.7 years) were enrolled between September 2014 and December 2015. Mean ± standard deviation of baseline glycated hemoglobin (HbA1c) and body mass index (BMI) were 7.7 ± 1.3% and 25.5 ± 4.6 kg/m2, respectively. The most prescribed medication as first-line treatment was dipeptidyl peptidase 4 inhibitors (53.7% of patients) followed by biguanides (21.4%), sulfonylureas (7.2%), and alpha-glucosidase inhibitors (6.8%). Second-line treatments included dipeptidyl peptidase 4 inhibitors (31.0%), biguanides (27.9%), sodium-glucose cotransporter 2 inhibitors (12.2%), and sulfonylureas (10.9%). First- and second-line treatments had different modes of action in 76.3% of patients. Those receiving first-line dipeptidyl peptidase 4 inhibitors were more likely to receive second-line biguanides and vice versa. Selection of second-line treatment was also associated with age, BMI, HbA1c, and renal function. CONCLUSIONS: This study showed the treatment reality and factors associated with choice of second-line treatment in Japanese patients with type 2 diabetes mellitus. The choice of second-line treatment was associated with age, BMI, HbA1c, renal function, and the mode of action of the first-line treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT02226822.