Diet and exercise are two of the commonest strategies to reduce weight. Whether a diet-plus-exercise intervention is more effective for weight loss than a diet-only intervention in the long-term has not been conclusively established. The objective of this study was to systemically review the effect of diet-plus-exercise interventions vs. diet-only interventions on both long-term and short-term weight loss. Studies were retrieved by searching MEDLINE and Cochrane Library (1966 – June 2008). Studies were included if they were randomized controlled trials comparing the effect of diet-plus-exercise interventions vs. diet-only interventions on weight loss for a minimum of 6 months among obese or overweight adults. Eighteen studies met our inclusion criteria. Data were independently extracted by two investigators using a standardized protocol. We found that the overall standardized mean differences between diet-plus-exercise interventions and diet-only interventions at the end of follow-up were −0.25 (95% confidence interval [CI]−0.36 to −0.14), with a P-value for heterogeneity of 0.4. Because there were two outcome measurements, weight (kg) and body mass index (kg m−2), we also stratified the results by weight and body mass index outcome. The pooled weight loss was 1.14 kg (95% CI 0.21 to 2.07) or 0.50 kg m−2 (95% CI 0.21 to 0.79) greater for the diet-plus-exercise group than the diet-only group. We did not detect significant heterogeneity in either stratum. Even in studies lasting 2 years or longer, diet-plus-exercise interventions provided significantly greater weight loss than diet-only interventions. In summary, a combined diet-plus-exercise programme provided greater long-term weight loss than a diet-only programme. However, both diet-only and diet-plus-exercise programmes are associated with partial weight regain, and future studies should explore better strategies to limit weight regain and achieve greater long-term weight loss.