The objective of this cross-sectional study was to identify the factors associated with health-related quality of life (HRQOL) of family caregivers of Chinese stroke patients. One hundred and twenty-three stroke patients consecutively admitted to a stroke clinic and their 123 family caregivers were recruited. The caregivers' HRQOLs were assessed with the Short Form 36 (SF-36). Two subscores of the SF-36, the Physical Component Summary and the Mental Component Summary Scores served as the dependent variables. Independent variables comprised patients and caregivers' demographic data and physical and psychological conditions in relation to caregivers' HRQOL. The severity of coexisting illnesses of both the patients and their caregivers was assessed using the Cumulative Illness Rating Scale. The Geriatric Depression Scale (GDS) was administered to rate both the patients and their caregivers' depressive symptoms. The extent of the patients' functional disability was assessed using the Barthel Index and the Instrumental Activities of Daily Living. Global cognition of the patients was measured using the Mini Mental State Examination. The level of social support and recent life events of the caregivers were rated using Lubben Social Network Scale and the Modified Life Event Scale, respectively. The multiple linear regression revealed caregivers' Cumulative Illness Rating Scale and GDS score were associated with Physical Component Summary Score of SF-36. The patients and caregivers' GDS score were associated with Mental Component Summary Score of SF-36. Severity of depressive symptoms in Chinese stroke patients and their caregivers is an important factor associated with the caregivers' HRQOL. Further studies evaluating interventions on caregivers' HRQOL should include the assessment and management of mood disorders.