Objective: To compare changes in quality of life (QoL) over 96 weeks in patients enrolled in a triple-therapy protocol, a treatment-intensification protocol, or an induction-maintenance therapy protocol, and to compare QoL between patients who continued and discontinued their antiretroviral regimen. Patients: Naive patients enrolled in a triple-therapy protocol (zidovudine/lamivudine or stavudine/didanosine or stavudine/lamivudine supplemented with protease inhibitor therapy of choice) (n = 35), a protocol of treatment intensification (ritonavir/saquinavir or ritonavir/saquinavir/stavudine) (n = 74) in which therapy was intensified with nucleoside analogue(s) in cases of insufficient viral suppression, and a protocol of induction (saquinavir/nelfinavir/lamivudine/stavudine) maintenance (saquinavir/nelfinavir or stavudine/nelfinavir) therapy (n = 50). Main outcome measure: Changes from baseline in QoL assessed by the Medical Outcomes Study HIV Health Survey at weeks 0, 12, 24, 36, 48, 72 and 96. Results: Patients in the triple-therapy and treatment-intensification protocols showed more favourable changes in physical function, social function, mental health, energy/fatigue, health distress and overall QoL compared to patients in the induction-maintenance protocol, with patients in the first two protocols showing improvements in QoL and those in the induction-maintenance protocol showing declining or unchanged QoL. Patients who discontinued study medication due to insufficient efficacy, toxicities or at their own request showed less favourable changes in QoL compared with patients who continued their regimen. The highest proportion of discontinuations was within the induction-maintenance protocol. Conclusion: Antiretroviral treatment strategies that are effective and tolerable have the potential to improve patients' QoL over 96 weeks.