OBJECTIVES: Oral Antidiabetics (OAD) have been shown to reduce the risk of mortality, particularly among metformin users, which had risk reductions of 36% for cardiovascular-related death and 33-40% for all-cause mortality. However, very few studies have assessed adherence to OAD and all-cause mortality. A population-based nested case-control study design was used to investigate the relationship between adherence to OAD and all-cause mortality among incident users of OAD. METHODS: Incident OAD users were identified using healthcare databases of residents covered by the public drug insurance plan of the Province of Quebec, Canada. Patients initiated OAD therapy between 2000 and 2009 and were aged 45-85 years at cohort entry. A nested case-control design was conducted to study mortality occurrence. Each case was matched to 10 controls by gender, age and duration of follow-up. The adherence to OAD was measured by calculating the medication possession ratio. Conditional logistic regression models were used to estimate the association between adherence to OAD and all-cause mortality adjusting for various potential confounders. RESULTS: The cohort included 63,859 incident OAD users at entry: mean age was 68 years old, 45% were male, 37% had coronary artery disease, 82% had hypertension, and 62% dyslipidemia. Most patients initiated their OAD treatment with biguanides (78%) and sulfonylureas (12%). The average follow up time was 48 months. Among those deemed adherent, the risk of mortality was decreased compared to nonadherent (Rate ratio: 0.67 [95%CI 0.64-0.70]). The likelyhood for mortality was higher for patients with heart failure (1.56 [1.49-1.65]), ≥ 2 cardiovascular diseases (1.45 [1.39-1.52]), amputations (2.03 [1.42-2.91]), chronic viral infections (1.73 [1.44-2.07]), corticosteroid use (1.69 [1.56-1.89]), and ≥ 1 hospital admissions (1.73 [1.65-1.80]). Conversely, mortality was least likely for patients with dyslipidemia (0.76 [0.73-0.79]), and hypertension (0.88 [0.83-0.94]). CONCLUSIONS: Adherence to OAD seems to be associated with a risk reduction of mortality. Further research is needed to confirm this risk. Residual confounding may remain a potential issue.