Background: Breast cancer diagnosis and treatment can have a profound influence on a woman's physical, psychosocial, and overall well-being. We examined the prevalence of depressive symptoms and its association with health-related quality of life (HRQOL) in women who are survivors of breast cancer. We also assessed if factors, including metastasis, cancer recurrence, diagnosis of new primary cancers, and comorbid conditions, are associated with depressive symptoms. Methods: The Patient Health Questionnaire (PHQ-8) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 were mailed to assess depressive symptoms and HRQOL, respectively, in breast cancer patients who received cancer treatment in a large tertiary cancer center. Results: Two hundred forty patients participated (56% response rate and 6-13 years since treatment). The mean score on the PHQ-8 scale was 4 points (standard deviation [SD] 4.8, median 2.0). Sixteen percent had PHQ-8 score ‡ 10 and were categorized as depressed. Depression was inversely associated with HRQOL subscales for functioning, financial, and global health and positively associated with symptoms. Logistic regression showed that younger age (odds ratio [OR] age in years 0.92, 95% confidence interval [CI] 0.86-0.99, p < 0.02), rheumatoid arthritis (OR 8.4,, p < 0.03), and years from treatment (OR 0.70, 95% CI 0.46-0.99, p < 0.05) were significant correlates of depression. Conclusions: Depression is a significant health concern for breast cancer survivors and is associated with lower HRQOL. The results suggest the need to monitor women with breast cancer for depression and provide resources for treating depression during the survival period.