OBJECTIVES: In daily practice many Type 2 Diabetes Mellitus (T2DM-)patients discontinue treatment. Therefore, the aim of this study was to investigate the determinants of (non-)persistence with oral antidiabetic drugs (OADs) in daily clinical practice. METHODS: From the PHARMO record linkage system, comprising among others linked drug-dispensing, and hospital data for >2.3 million subjects in the Netherlands, new users of OADs were identified in the period 1999-2005. Patients with =1 year of follow-up, were included in the study-cohort. Persistence with OAD-treatment in the first year of therapy was determined using the method of Catalan. Potential determinants of (non-)persistence included patient-characteristics, type of initial OAD-therapy, and cardiovascular co-morbidity. RESULTS: The study included 33,299 new users of OADs. One year after start, 42% of new T2DM-patients had stopped using any OAD. The risk of non-persistence was decreased with male gender (HR: 0.97; 95% CI: 0.94-1.00), and cardiovascular drug use (HR: 0.91; 95% CI: 0.86-0.97). Regarding age, compared to patients =76 years, the age-group 55-75 years had a 16% lower risk, and the age-group 30-44 years had a 32% increased risk of non-persistence. Patients starting on combined metformin+SU had a lower risk of non-persistence with any OAD; compared to patients starting on metformin monotherapy, the risk was 23% lower (HR: 0.77; 95% CI: 0.70-0.85). The risk of non-persistence was increased with a specialist as first prescriber (HR: 1.20; 95% CI: 1.15-1.26), higher initial daily dose (HR: 1.09; 95% CI: 1.00-1.22), and higher initial daily dosing frequency (HR: 1.10; 95% CI: 1.02-1.20). CONCLUSION: In daily clinical practice about 40% of new T2DM-patients stop OAD-therapy within one year. Determinants of stopping OAD-medication were male gender, age-group, specialist as first prescriber, dosing, cardiovascular drug-use, and type of initial OAD-treatment.