Perceived quality of life (QoL) and psychological well-being represents an important target of secondary prevention practice in post-stroke patients. We aimed to identify the major covariates of impaired QoL in stable post-stroke patients and whether impaired QoL itself represents independent mortality predictor.The study consisted of a cross-sectional and a prospective part. Three hundred forty-one patients [mean age 69.0 (SD 9.1)] were interviewed at least 6 months after discharge from hospital for their first-ever ischemic stroke. QoL was objectivized using 36-Item Short-Form Health Survey (SF-36) scoring. Standard health-related questionnaires, including Hospital Anxiety and Depression Scale (HADS), risk factors, and biochemical markers, were assessed. To estimate the 5-year all-cause and cardiovascular mortality, we ascertained the vital status and declared cause of death.Anxiety, depression (HADS score ≥11), brain natriuretic peptide levels ≥100 ng/mL, residual motor impairment at interview, Rankin Scale ≥4 at discharge from hospitalization, and raised blood pressure were identified as main determinants of impaired QoL in the cross-sectional part. The 5-year all-cause and cardiovascular mortality rates were 25.8 and 19.9 %, respectively. After adjustment for potential covariates, patients with an SF-36 score ≤40 at baseline had more than a twofold higher risk of all-cause and cardiovascular mortality (with HRRs 2.01 (95 % CI 1.21-3.32), p < 0.007 and 2.32 (95 % CI 1.32-4.09), p < 0.003, respectively) during the 5 years of follow-up.In conclusion, anxiety, depression, and raised brain natriuretic peptide levels were the most important covariates of impaired QoL in post-stroke patients. Moreover, a decreased SF-36 score (≤40) represents an independent surrogate of increased additive mortality risk.