The aim of this study was to examine the effect of weight loss on health-related quality of life (HRQL) in randomized controlled intervention trials (RCTs). MEDLINE, HealthStar and PsycINFO were searched. RCTs of any weight loss intervention and 20 HRQL instruments were examined. Contingency tables were constructed to examine the association between statistically significant weight loss and statistically significant HRQL improvement within five HRQL categories. In addition, Short Form-36 (SF-36) outcomes were pooled using random-effects models. Fifty-three trials were included. Seventeen studies reported statistically significant weight loss and HRQL improvement. No statistically significant associations between weight loss and HRQL improvement were found in any contingency table. Because of suboptimal endpoint reporting, quantitative data pooling could only be performed using 25% of SF-36 trials in any one model. Significant improvements in physical health were found: mean difference 2.83 points, 95% CI 0.55–5.1, for the physical component score, and mean difference 6.81 points, 95% CI 2.99–10.63, for the physical functioning domain score. Conversely, no significant improvements in mental health were found. No significant association was found between weight loss and overall HRQL improvement. Weight loss may be associated with modest improvements in physical, but not mental, health.