This review aims to assess by meta-analysis of randomised controlled trials (RCTs) changes in pain and function when overweight patients with knee osteoarthritis (OA) achieve a weight loss. Systematic searches were performed and reference lists from the retrieved trials were searched. RCTs were enclosed in the systematic review if they explicitly stated diagnosis of knee OA and reported a weight change as the only difference in intervention from the control group. Outcome Measures for Arthritis Clinical Trials III outcome variables were considered for analysis. Effect size (ES) was calculated using RevMan, and meta-regression analyses were performed using weighted estimates from the random effects analyses. Among 35 potential trials identified, four RCTs including five intervention/control groups met our inclusion criteria and provided data from 454 patients. Pooled ES for pain and physical disability were 0.20 (95% CI 0 to 0.39) and 0.23 (0.04 to 0.42) at a weight reduction of 6.1 kg (4.7 to 7.6 kg). Meta-regression analysis showed that disability could be significantly improved when weight was reduced over 5.1%, or at the rate of >0.24% reduction per week. Clinical efficacy on pain reduction was present, although not predictable after weight loss. Meta-regression analysis indicated that physical disability of patients with knee OA and overweight diminished after a moderate weight reduction regime. The analysis supported that a weight loss of >5% should be achieved within a 20-week period--that is, 0.25% per week.