This study investigates the relationship between current symptom status (no symptoms vs. symptoms present) and dimensions of health-related quality of life and overall quality of life (QoL) (poor vs. good) of 612 people living with HIV, just prior to initiating highly active antiretroviral therapy at three public hospitals in KwaZulu-Natal, South Africa. The mean number of symptoms reported on the day of interview was 8.4. Experiencing symptoms was most reported by patients in receipt of a disability grant, patients who did not have enough money to meet basic needs, who experienced negative feelings less, who had prayed in the last 6 months and who reported better QoL. Higher QoL was in turn associated with experiencing negative feelings less, praying, receiving a disability grant and having enough money to meet basic needs. Physical health and independence were important predictors of higher QoL for patients both with and without symptoms. Psychological health and spirituality may however mediate the effects of HIV symptoms and socioeconomic stressors.