Sub-Saharan Africa bears the largest public health burden of Kaposi sarcoma (KS), a leading cause of cancer mortality. Quality of life (QOL) assessments in cancer patients can provide information on prognosis beyond traditional biomarkers or biological measures. The prognostic value of QOL measures in patients with HIV-KS was evaluated. Prognostic associations of baseline QOL scores (by quartiles or thresholds for clinical importance) and changes in QOL scores (using minimum important difference) over the first 3 months of therapy were evaluated in 112 participants with HIV-KS randomised to receive ART, with or without chemotherapy. Cox's regression analysis assessed the prognostic contribution of QOL scores from the EORTC QLQ-C30 questionnaire. Survival curves were generated using the Kaplan-Meier method. Baseline QOL scores did not predict overall survival. The change in the 3-month QOL scores for the global health scale, fatigue, and pain domains was prognostic; the hazard ratios were 3.88 (95% CI 1.32-11.38, p = 0.01), 3.72 (95% CI 1.61-8.62, p = 0.00) and 5.96 (95% CI 2.46-14.43, p = 0.00), respectively. QOL assessments can provide useful prognostic information in patients with HIV-KS. Patients lacking meaningful improvement early into treatment represent a population at high risk of death.