Abstract Introduction: Patients with breast cancer are at increased risk for depression and suicide compared to the general population. Breast cancer is unique among other cancers in that some treatments aim to decrease levels of estrogen, a hormone that is intricately linked to mood regulation. The trauma of diagnosis, invasive treatments, and hormone dysregulation all possibly contribute to poor mental health outcomes. Understanding risk factors associated with depression and distress are important for timely interventions. Methods: We performed a retrospective chart review of breast cancer patients seen at Froedtert & MCW Cancer Center Breast Care Clinic between 2019 and 2020. The present study had two aims. The primary aim was to identify breast cancer patient populations at increased risk of depression and psychological distress. Patient populations were distinguished by tumor pathology, patient demographics, and types of treatment interventions. The secondary aim was to identify demographic and clinical variables associated with changes in self-reported distress and depression. Univariate and multivariate analysis of demographic and clinical variables was performed in relation to Patient Health Questionnaire (PHQ) and The National Comprehensive Cancer Network (NCCN) Distress Thermometer scores. Results: Data from 197 patients was analyzed. Patients with a history of depression scored significantly higher on distress screening (mean= 4.4 3.0, p=0.004) versus patients without psychiatric history (mean 2.8 2.9). Patients under 50 years old reported higher levels of distress than patients over 70 years old (p=0.031, beta= -1.0). Self-reported distress declined significantly with increased time from initial diagnosis (p=0.043; p=0.006 at 2 years). Distress was significantly higher prior to initiation of radiation versus during and immediately following therapy (p=0.028). A history of depression, younger age, passage of time, and temporal relationship to radiation treatment were not associated with significant differences in self-reported depression on multivariate analysis. Distress and depression screening scores were not significantly impacted by surgery or chemotherapy (p=0.5; p=0.11 respectively). Conclusion: Patients with a known history of depression and age less than 50 reported significantly higher levels of distress but not depression associated with diagnosis of breast cancer. Distress exhibited a greater downward trend than depression following initiation of oncologic intervention. The results of this study indicate that breast cancer patients are susceptible to significant fluctuations in psychological distress. In contrast, clinically relevant depression screening scores were less frequent and less subject to deviation. Table 1. Multivariate analysis. Citation Format: Kelly R. Cotchett, Adam H. Kelly, Aniko Szabo, Yee Chung Cheng, Sailaja Kamaraju, Christopher Chitambar, Lyndsey Wallace, Lubna N. Chaudhary, John Burfeind. Depression and Psychological Distress in Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-34.