This study explored predictors of clinically meaningful improvement in health-related quality of life (HRQOL) among obese patients completing a specialist weight management programme. One hundred and ninety-nine adults aged from 20–88 with a BMI >30 with comorbidities or BMI>35 with/without comorbidities were sampled. The results suggested that both weight loss and changes in depression were significant predictors of HRQOL improvement. However, predictors differed between weight loss groups. Clinically meaningful improvement in HRQOL was found to be due to weight loss when participants had lost 5 kg or more in weight. In contrast, among individuals who lost 0.1–4.9 kg, improvement in HRQOL was accounted for by positive changes in depression scores.