The purpose of this study was to examine the relationship between the presence of clinical depression and persistence to drug therapy treatment for depression with early nonpersistence to antihypertensive therapies in a large, diverse cohort of newly treated hypertension patients. Using a hypertension registry at Kaiser Permanente Northern California, the authors conducted a retrospective cohort study of 44,167 adults (18 years and older) with hypertension who were new users of antihypertensive therapy in 2008. We used multivariate logistic regression analysis to model the relationships between the presence of clinical depression and early nonpersistence (defined as failing to refill the first prescription within 90 days after the end of the first fill days’ supply) to antihypertensive therapies, controlling for sociodemographic and clinical risk factors. Within the group of 1484 patients who had evidence of clinical depression in the 12 months prior to the initiation of antihypertensive therapy, the authors examined the relationship between drug therapy treatment for depression and 6-month persistence with antidepressant therapy with early nonpersistence with antihypertensive therapies. No association was found between the presence of clinical depression and early nonpersistence to antihypertensive therapies after adjustment for individual demographic and clinical characteristics and neighborhood-level socioeconomic status. However, among the subset of 1484 patients with documented evidence of clinical depression in the 12 months prior to the initiation of antihypertensive therapy, being prescribed and persistence with antidepressant therapy was strongly associated with lower odds of early nonpersistence to antihypertensive medications (odds ratio, 0.64; confidence interval, 0.42-0.96). In an integrated delivery system, the authors found that treatment for depression was associated with higher levels of antihypertensive persistence. Improving quality of depression care in patients with comorbid hypertension may be an important strategy in decreasing cardiovascular disease risk in these patients.