OBJECTIVES: Despite the growing use of antidepressants (AD) and the potential grave consequences of inadequate treatment, little is known about the impact of adherence to AD treatment on mortality in the general population. This study aimed to evaluate the association between adherence to AD and all-cause mortality in a population-based cohort. METHODS: Data were extracted from the electronic medical database of the largest health provider in Israel, covering 53% of Israel's population, and a total of 251,746 patients were included who had purchased AD at least once and were older than 40 years of age, between 2008-2011. Adherence was measured as mean possession ratio (duration of supplied AD divided by duration of prescribed AD) and was modeled as a four level variable: non-adherence (<20%), poor (20%-50%), moderate (50% - 80%), and good (>80%) adherence. We used survival analyses and included demographic and clinical variables to determine the adjusted association between AD adherence and mortality. RESULTS: The poor, moderate and good adherence groups had adjusted mortality hazard ratios of 0.93 [95% Confidence interval (CI): 0.89 to 0.97], 0.83 [95% CI: 0.79 to 0.86] and 0.88 [95% CI: 0.85 to 0.91], respectively, with corresponding p-values <0.0001 for all comparisons, compared to the non-adherent group. CONCLUSIONS: Adherence to AD, even at low levels, is associated with a corresponding decrease in the risk of mortality, controlling for relevant covariates. Physicians from all disciplines should actively improve their patients' adherence to AD since their persistent use is associated with increased survival.