Abstract Results from studies of the impact of psychological stress on breast cancer risk have been inconsistent, possibly due to differences in subjective responses to similar stressful events. Dispositional optimism, characterized by the general belief that good things will happen in one's life, is correlated with better adjustment to diverse stressors and psychological wellbeing. Limited numbers of studies suggest that the benefit of optimism may also extend to physical health. The purpose of the present analysis was to examine psychosocial and behavioral correlates of dispositional optimism and to determine whether optimism is a protective factor for breast cancer in a large cohort of women aged 35-74 years. Data came from the Sister Study, a prospective cohort of 50,884 women with a sister with breast cancer. Optimism was assessed among 46,776 women (92%) at the first biennial follow-up interview using the 6-item Life Orientation Test –Revised (LOT-R). After excluding 1,009 women diagnosed with breast cancer prior to the biennial survey, the present analysis comprised 45,767 women. Each item of the LOT-R was scored from 1 (strongly disagree) to 5 (strongly agree). Based on the average score, women were categorized into 3 groups: low (<3); modest (3-<4); and high optimism (>=4). Between the biennial survey and March 2015, 1,398 women were newly diagnosed with breast cancer with an average follow-up duration of 859 days. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for breast cancer were estimated using Cox proportional hazards regression. Approximately half of women (50.9%) fell into the high optimism category, followed by modest (40.4%) and low (8.8%) optimism categories. Women with high optimism were older and reported having higher education and income than those with lower optimism. They were also more likely to exercise, eat healthily, and maintain a healthy weight, and less likely to smoke. Compared with women with modest or high optimism, those with low optimism more frequently reported experience of stressful life events during childhood (mean number of 2.2 in low; 1.3 in modest and 1.0 in high optimism groups) and adulthood (5.2 in low; 4.3 in modest and 3.9 in high optimism groups). Low optimism was also highly correlated with lack of emotional support (14% in low; 4.1% in modest and 1.3% in high optimism group) and increased depression score (14.2 in low; 10.2 in modest and 8 in high optimism group). Compared to the modest optimism group, high optimism was associated with reduced risk of breast cancer, after adjustment for sociodemographic, behavioral, reproductive and psychological variables (adjusted HR: 0.82, 95% CI: 0.72-0.93). Although not statistically significant, low optimism also had a protective association with breast cancer (adjusted HR: 0.84, 95% CI: 0.67-1.06). A sensitivity analysis that excluded 292 breast cancer cases diagnosed within 1 year from the biennial survey yielded similar results. We also performed an exploratory subgroup analysis. The protective association with high optimism appeared to be more evident among women aged <60 years (HR=0.79; 95% CI:0.67-0.92) and minority women (HR=0.69, 95% CI: 0.49-0.96) compared to those aged 60 or older (HR=0.94; 95% CI: 0.81-1.11) and non-Hispanic whites (HR=0.89, 95% CI: 0.79-1.00), but there was no statistical evidence for heterogeneity (p values for heterogeneity = 0.23 for age and 0.26 for race/ethnicity, respectively). No significant interaction with optimism was found for tumor subtype, menopause status, and number of 1st degree family members with breast cancer. In conclusion, we found a reduced breast cancer risk among women with high optimism. High optimism was positively correlated with higher socioeconomic status, healthy behaviors, and reduced stressful life events and depression, but these factors did not explain the protective association between high optimism and breast cancer risk in our data. Citation Format: Sangmi Kim, Fengjiao Hu, Lisa DeRoo, Helen Meier, Christine Parks, Dale Sandler. Optimism and breast cancer risk: Results from a prospective cohort study. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C39.