Objective: To compare the impact on quality of life (QoL) of omeprazole and misoprostol during healing, and omeprazole, misoprostol, and placebo during maintenance treatment in chronic NSAID users with NSAID-associated gastroduodenal lesions. Methods: Validated baseline and follow-up QoL questionnaires were completed by 610 patients (healing: after 4.8 weeks: maintenance: after 6 months). Results: Patients with arthritis being treated with NSAIDs have a poor QoL. Rheumatoid arthritis causes more joint problem. and physical mobility limitations than osteoarthritis. Chronic NSAID use causes heartburn and dyspepsia. QoL improved on both treatments (about equally on two general QOL scales), but omeprazole relieved gastrointestinal symptoms more than misoprostol, particularly reflux. abdominal pain and indigestion symptoms, During maintenance, both treatments maintained QoL, but misoprostol induced diarrhoea, Conclusion: QoL in arthritis patient, on chronic NSAID treatment is destroyed. Omeprazole is superior to misoprostol for relief and prevention of NSAID-associated gastrointestinal symptoms allowing continued NSAID treatment without compromising the patients' QoL.