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To evaluate the association between upward dose titration of antidepressants and medication adherence during the first 6 months of a newly initiated antidepressant treatment for patients with major depressive disorder (MDD).We conducted a retrospective observational cohort study using Thomson Reuters MarketScan Commercial Claims and Encounters Claims data. We identified 40,873 patients aged 18–64 with MDD newly initiating a selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, or bupropion between July 1, 2005 and June 30, 2007. Patients with titration (defined as antidepressant initiation at doses equal or lesser than American Psychiatric Association treatment guidelines with a dosage increase in the first 60 days of treatment) were compared to patients with no titration. Adherence was measured as the proportion of days covered (PDC) on antidepressant treatment. Patients with PDC ≥ 80% were considered adherent. Persistence was measured as the duration of time from initiation to a 30-day gap in antidepressant treatment. Multivariate logistic regression and Cox-proportional hazard models examined the influence of titration on adherence and persistence, respectively.Adherence was greater in the titration group than in the nontitration group (67.5% versus 45.2%, P < .01). After adjustment for selected covariates, patients in the titration group were more likely to adhere to antidepressant treatments (odds ratio = 2.60, 95% confidence interval (CI) = 2.47–2.74) and less likely to have a 30-day gap in treatment (hazard ratio = 0.48, 95% CI = 0.45–0.51).Upward dose titration on antidepressant treatments was associated with improved medication adherence and persistence. For clinicians initiating antidepressant treatment, titrating antidepressant doses may improve patient outcomes.