SummaryAimsThis study explored the association between enlarged perivascular spaces (EPVS) and the health‐related quality of life (HRQoL) in patients with acute ischemic stroke.MethodsThis was an observational study of consecutively screened patients with acute ischemic stroke from March 2010 to March 2015. EPVS were rated in the basal ganglia and the centrum semiovale with a validated scale. The HRQoL was assessed 3 months after the stroke onset using the Stroke‐Specific Quality of Life (SSQoL). Linear regression models were used to study the association between EPVS and HRQoL.ResultsThe study included 648 patients (mean age 65.8 years; 40.0% women) with mild to moderately severe stroke (median NIHSS score 2), of whom 640 (98.8%) exhibited signs of small vessel disease. The median EPVS scores in the basal ganglia and the centrum semiovale were 1 each. In linear regression analysis, EPVS in the basal ganglia were associated with a lower total SSQoL score (P = 0.02) and lower mobility (P = 0.01), mood (P = 0.03), and self‐care (P < 0.01). EPVS in the centrum semiovale were associated only with a lower SSQoL work/productivity subscore (P = 0.002).ConclusionsEPVS are associated with lower HRQoL in patients with mild to moderate acute ischemic stroke. Early identification and intervention of EPVS may improve HRQoL in stroke survivors.