Background: One of the most important outcomes following bariatric surgery is an improvement in health-related quality of life (QOL). This study aimed to explore what degree of weight loss is required after bariatric surgery in order to achieve a clinically significant change in QOL from pre-surgery to 4 to 5 years after surgery. Methods: Participants were assessed prior to having surgery (N = 280) and were invited to participate in a follow-up study 4 to 5 years after surgery. Sixty-seven of the original participants agreed to take part and completed a Web-based survey, which included the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire. Several analyses were conducted to examine the association between weight loss and clinically significant change in QOL. Results: Mean age was 48.13 ± 10.37 years, 51 (76%) were female, 62 (92.5%) Caucasian, and mean baseline body mass index (BMI) was 41.11 ± 6.03 kg/m2. The mean percent of excess weight loss (EWL) was 46% (17% total weight loss), and 64% (n = 43) achieved a clinically significant change in QOL. The majority of those who lost ≥40% EWL had a clinically significant change in QOL, and their odds of achieving this change were 2.81 times higher than those that did not. Conclusions: Results indicated that an EWL of ≥40% may be sufficient for the majority of patients to achieve clinically significant change, but that ≥50% is a better predictor of clinically significant change.