Background and Purpose-For the survivors, activities of daily living, handicap, and depression have a significant impact on health-related quality of life (HRQOL). How the dynamic changes of these variables relate to HRQOL over time in the subacute phase of stroke recovery has not been investigated. The objective of this study was to study longitudinal behaviors of HRQOL of the stroke survivors in relation to the changes in activities of daily living, handicap, and depression after stroke. Methods-This was a prospective cohort study of first disabling patients with stroke. Subjects were interviewed at 3, 6, and 12 months after stroke for modified Barthel Index, London Handicap Scale, Geriatric Depression Scale, and the World Health Organization Quality of Life questionnaire (abbreviated Hong Kong version). A latent curve model was developed to analyze how the dynamic changes in activities of daily living, handicap, and depressive mood related to the changes in HRQOL. Results-Two hundred forty-seven of 303 patients (82%) followed up at 3 months after stroke could complete the quality-of-life questionnaire. Their mean age was 68.8 years. The latent curve model analysis revealed that initial physical health HRQOL was independently associated with activities of daily living, handicap, and depression. The other 3 HRQOL domain scores were primarily associated with depression only. The rates of change in all 4 domains of HRQOL were significantly and inversely associated with rate of change in the Geriatric Depression Scale only. Conclusion-Change in mood in the postacute phase of stroke recovery is the most significant determinant of change in HRQOL. More attention should be paid to the detection and management of poststroke depression.