Background: Tamoxifen (TAM) and aromatase inhibitors (AI) are associated with a high side-effect burden including depression and cognitive deficits which compromise quality of life and adherence to treatment. The aims of the study were to determine the efficacy of antidepressants (AD) with hormone mediated depression in ER+ breast cancer patients and to determine if any clinical variables predicted successful AD treatment response. Methods: A retrospective chart review of consecutive referrals to psycho-oncology of breast cancer patients on TAM or AI with new onset depression was conducted. Demographic variables, cancer stage and treatment, hormonal treatment, psychiatric history and AD treatment were collected. Assessments for depression, anxiety and cognitive disorders included clinical interviews, patient-rated scales [Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI)] and a clinician-rated scale [Montreal Cognitive Assessment (MoCA)]. These measures were done at baseline (before starting an AD) and follow-up to determine AD treatment response. Successful AD treatment is defined as ≥50% reduction in baseline BDI score, while remission of depression is defined as a BDI score < 8. Statistical analysis comparing clinical variables between AD responders and non-responders included Fischer’s exact test or chi-square, one-way ANOVA, t-test, and binary logistic regression to determine which variables predicted successful AD treatment response. Results: A sample of 40 ER+ breast cancer patients (mean age 55 years; 39 females, 1 male; 26 Hispanic, 14 non-Hispanic) included 18 on TAM and 22 on AI. AD included venlafaxine (N = 18), escitalopram (N = 9), bupropion (N = 4), mirtazapine (N = 4), sertraline (N = 3) and duloxetine (N = 2). Over 72% (29/40) of patients successfully responded to AD with a complete depression remission rate of 50% (20/40). Venlafaxine at a mean dose of 150 mg was significantly more effective (p = .013) in treating hormone-mediated depression when compared to selective serotonin reuptake inhibitors (SSRIs) and other AD (bupropion, mirtazapine). Specifically, 94% (17/18) of patients on venlafaxine successfully responded. Other variables such as cancer stage and treatment, demographics, psychiatric history, and specific hormonal therapy did not predict AD treatment response. Conclusions: Venlafaxine 150 mg daily yielded significantly higher rates of AD response and complete remission of depression in ER+ breast cancer patients with TAM-induced and AI-induced major depression. Venlafaxine was significantly more effective than SSRIs and atypical AD. This high rate of response is likely due to dual serotonin and norepinephrine reuptake inhibition achieved at 150 mg dosing. Venlafaxine can be safely administered with TAM.