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Background: Although poststroke depression is a common and devastating consequence of stroke, few studies have examined the occurrence and correlates of developing depression among stroke survivors without a history of depression before the stroke. Hypothesis: Using data on post-menopausal women from the Women’s Health Initiative (WHI), we estimated the odds of new-onset depression poststroke (NDPS) and assessed the associations of psychosocial and other factors with NDPS. Methods: We analyzed data from 1433 respondents who were stroke-free at enrollment and had no self-reported history of depression prior to their non-fatal ischemic stroke, and had information regarding stroke severity. NDPS was assessed in the five-year period after stroke using the Center for Epidemiologic Studies Depression Scale or new antidepressant medication use. Unadjusted 5-year depression rates are presented by demographic, comorbid, and psychosocial factors measured pre-stroke. Vascular territory of stroke is given by the Oxfordshire classification. Logistic regression provided odds ratios of NDPS controlling for multiple covariates. Results: New-onset depression post ischemic stroke occurred in 21.4% (306/1433) of the analytic cohort and varied by stroke outcome as measured by the Glasgow scale ranging from 16.7% of those with good recovery to 31.5% of those severely disabled. Women with total anterior circulation infarction had the highest level (45.8%) of NDPS while those with lacunar infarction had the lowest (19.1%). Among those with ischemic stroke and good recovery (n=754), moderate level of optimism was associated with a reduced odds of NDPS (compared to low optimism, OR, 0.29; 95%CI, 0.14-0.63) adjusting for demographics, behavioral factors, and comorbidities. Cynical hostility, social support, and traumatic life events were unassociated with NDPS. Conclusions: New-onset depression is common after ischemic stroke among post-menopausal women. Though rarely studied in poststroke depression, psychosocial factors (specifically optimism) may play a role in reducing risk for new-onset depression after stroke.