This study examines the relationships among illness-related factors, stress, health-related quality of life (HRQOL), and psychological distress in persons infected with the human immunodeficiency virus (HIV) living in Hong Kong (N = 55). Participants completed questionnaires including a Symptom Checklist, Modified HIV Stressor Scale (HIVSS), Medical Outcomes Study Short-Form 36 (SF-36), and the Hospital Anxiety and Depression Scale (HADS). In addition, CD4 count information was obtained. Multiple regression analyses were used to model the SF-36 and HADS scores as a function of illness-related factors as well as the stress count and intensity. The number of symptoms was found to be inversely related to SF-36 general health and positively related to the HADS anxiety score. However, CD4 count did not have any significant association with any of the scales on the HRQOL or psychological distress. After controlling for the effect of symptoms, the HIVSS stress count still accounted significantly for additional variance in both HADS anxiety and depression as well as the SF-36 social functioning and role-emotional scores. The study supports the possible contribution of psychosocial factors to the HRQOL and psychological distress after controlling for illness-related factors. Results are discussed in the context of characteristic social factors and services in Hong Kong.