Background: Whether the time course of post-stroke depression (PSD) can be used to predict the quality of life (QoL) of patients with late-stage stroke remains unclear, this study investigated whether persistent depression at 1 year after stroke predicts QoL at 5 years following stroke. Methods: We analyzed the demographic and clinical data of patients with stroke in 56 hospitals across China that participated in the Prospective Cohort Study on the Incidence and Outcome of Patients with PSD in China Study. Follow-up assessments were performed at the following time points after stroke: in person, 2 weeks, 3 months, 6 months, and 1 year; by telephone, 5 years. National Institutes of Health Stroke Scale (NIHSS) score on admission, recurrence, disability, depression, QoL, and chronic complications were recorded. Depression was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders. QoL was measured using short form-12 (SF-12). Multivariable ordinal logistic regression analysis was used to identify factors that independently affected the physical component summary (PCS) and mental component summary (MCS) scores of the SF-12. Results: Of the 801 patients evaluated in this study, 80 had persistent depression. The multivariable regression analysis of data obtained at 5 years showed that persistent depression at 1 year (odds ratio [OR]: 0.48; 95% confidence interval [CI]: 0.29-0.81) and disability at 5 years (OR: 0.34; 95% CI: 0.23-0.49) were associated with poor MCS scores at 5 years. Old age, a high NIHSS score on admission, disability at 5 years, and stroke recurrence within 5 years were associated with poor PCS scores at the 5-year follow-up. Conclusions: Persistent depression at the 1-year follow-up could predicted poor MCS scores at the 5-year follow-up. The development of interventional strategies targeting post-stroke patients with persistent depression is warranted. © 2019 The Chinese Medical Association, produced by Wolters Kluwer, Inc.