In a prospective cohort study between February 2001 and January 2004, baseline and 12-month follow-up data were collected on 226 and 197 men with HIV infection at three infectious disease clinics in a southern state, respectively. While many studies have provided important information on the correlates of health-related quality of life (HRQOL) during HIV infection, little research attention has been directed toward examining the impact of factors on change in HRQOL over time. This study evaluated changes in HRQOL, and examined whether baseline active coping, family social support, depressive symptoms and CD4 cell counts predicted HRQOL changes over time among men with HIV infection. Patients' HRQOL, social support and depressive symptoms were measured with the HIV Cost and Services Utilization Study tool, Coping with HIV Questionnaire, Social Support Appraisals Scale, and Centers for Epidemiological Studies Depression instrument. Multivariate linear regression analyses were conducted to determine the time-related effects of the psychosocial variables and CD4 cell counts on each HRQOL dimension. Our results indicated that higher family support and CD4 cell counts at baseline were predictive of improved changes in physical and social functioning over time, and higher depressive symptoms at baseline were predictive of diminished role functioning, emotional well-being, and general health perception. These findings underline the importance of enhancing family social support, identifying and treating depression, and improving immune function to optimize HRQOL among men with HIV infection.