Background Many patients with cerebral infarction suffer from symptoms such as pain, fatigue, and depression. The aim of this study was to evaluate these symptoms in relation to health-related quality of life (HRQoL) on long-term follow-up. Materials and methods All surviving stroke patients admitted to the Stroke Unit, Haukeland University Hospital, Norway between February 2006 and November 2008 were sent a questionnaire, including a visual analog pain scale, Fatigue Severity Scale, Depression Subscale of Hospital Anxiety and Depression Scale, Barthel Index, and three measures of HRQoL – 15D, EuroQol, and EuroQol Visual Analogue Scale – at least 6 months after stroke onset. Cox regression survival analysis, including EQ-5D, was performed by November 2009. Results The questionnaire was returned by 328 patients. All three symptoms were reported by 10.1% of the patients, and 26% reported two symptoms. There was a significant association between worse HRQoL scores and an increasing number of cooccurring symptoms for all three HRQoL scores. Fatigue, depression, pain, functional state, and sleeping disorder on follow-up accounted for 58%–83% of the variability in HRQoL, depending on which HRQoL scale was used. Cox regression analysis showed that mortality was associated with a low EuroQol score (P = 0.016). Conclusion Pain, fatigue, and depression were common symptoms among these stroke patients and, to a large extent, they determined the patients’ HRQoL. Low HRQoL was associated with increased mortality.