Despite rehabilitation, stroke patients continue to have impaired function and reduced health-related quality of life (HRQoL) even in a chronic stage. However, no clear information is available on long-term variations in HRQoL. In this study, we aimed to report the short- and long-term changes in HRQoL in a subacute stroke sample that was enrolled in a clinical trial on arm rehabilitation. Thirty-nine stroke survivors (62% male, mean age 68 years) were assessed using the Stroke Impact Scale Version 2.0 (SIS 2.0) pre and post rehabilitation and at 6 months and 6 years follow-up. Long-term changes in physical function were explored through clinically meaningful changes in the Stroke Impact Scale-16 (SIS-16). After rehabilitation (P < .001), an overall improvement was found in all SIS domains except the memory and thinking, emotions, and communication domains. The baseline SIS-16 score (P < .001), the presence of a sensory deficit, and rehabilitation setting (P < .05) were factors related to the SIS-16 domain scores at the end of rehabilitation and at 6 months follow-up. Patients showed the most deterioration in the mobility (P < .001), strength (P < .003), and hand function (P < .05) domains 6 years after stroke. Stroke severity, male gender, and age ⩾65 years are related with a long-term HRQoL reduction after stroke.