Introduction: Impaired adherence is common among patients using antidepressant drugs (ADs). However, few studies investigated the role of age and gender in adherence to AD and finding conflict. Objective: This study aimed to determine how gender and age impact adherence to AD in a large-scale cohort. Methods: We conducted a historical cohort study (N∈=∈310,994 individuals) that claimed AD prescriptions during a 4-year period. Adherence was defined as the ratio between the duration of claimed AD prescriptions and the duration of continuously prescribed AD. Results: Substantial differences in the mean adherence to AD were noted throughout the lifespan, ranging from 0.38 (first decade) to 0.63 (tenth decade). Average adherence was significantly higher for males aged 20-40 years than for females of that age, but this relationship reversed later in life (50-70 years). A regression analysis model of adherence as the dependent variable showed a significant interaction between age and gender variables (beta∈=∈0.001, p∈<∈0.0001). Conclusions: This study demonstrates the effect of age and gender, and their interaction, on adherence to AD across the entire life span. The marked age-and modest, yet significant, gender-related effects should be taken into consideration when targeting impaired adherence to these commonly prescribed medications.