This study examined the relationships among comorbid conditions, symptom stress, depression, functional status and health-related quality of life (HRQOL) in low-income older African Americans with chronic diseases. A convenience sample of 83 older African American adults living in subsidized housing for elders participated in the study. Data were collected in face-to-face interviews. Participants reported lower scores on HRQOL than the SF-36 norms for age 60 or older in the general U.S. population. Comorbid conditions, symptom distress, depression, and functional status significantly predicted both the physical (F = 38.92, p < .001) and mental (F = 23.21, p < .001) health components of HRQOL, accounting for 63% of variance in the SF-36 physical health score and 55% of the variance in the SF-36 mental health score. The findings suggested that developing interventions to assist older African Americans to better manage their symptoms and depression are of prime importance for improving HRQOL.