OBJECTIVES: To evaluate in a prospective, randomized clinical trial (RCT), symptom response among obese knee osteoarthritis (OA) patients following a feasible, intensive weight-loss program for 16 weeks. METHODS: Eligible patients were obese [body mass index (BMI)>30kg/m(2)]; >50 years old, with primary knee OA. Participants were randomized to either a very-low-energy diet (VLED) or a low-energy diet (LED) (415kcal/day and 810kcal/day, respectively), using commercially available formula foods - only for the first 8 weeks, managed by dieticians. Followed by an additional 8-week period of a hypo-energetic diet consisting of normal food plus meal replacements (1200kcal/day). The primary endpoint was the number of patients responding according to the Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) responder criterion. The statistical analysis was based on a non-responder intention-to-treat (ITT) population (baseline observation carried forward). RESULTS: One hundred and ninety two patients (155 (80.7%) females) with a mean age 62.5 years [standard deviation (SD) 6.4; range 50-78 years]; average BMI 37.3 (SD 4.8) were included. At 16 weeks, similar proportions of the VLED and LED groups, 59 (61.5%), and 63 (65.6%) patients, respectively, met the OMERACT-OARSI responder criteria, with no statistical significant difference between the groups (P=0.55). Combining the groups the pooled estimate was 64% meeting the responder criteria [95% confidence interval (CI) 57%, 70%]. There was an overall reduction in pain, corresponding to an average pain reduction on the visual analogue scale (VAS) of 11.1 (95%CI 13.6, 8.5) in the combined groups. At week 16 weight loss in the combined groups was 12.8kg (95%CI: 11.84-13.66; P<0.001). 71% lost >/=10% body weight in both diet groups, with a pooled estimate of 74% (95%CI: 68-80%). CONCLUSION: No clinically significant differences were found between the 415kcal/day and 810kcal/day diets. A 16-week formula-diet weight-loss program resulted in a fast and effective weight loss with very few adverse events resulting in a highly significant improvement in symptoms in overweight patients with knee OA. ClinicalTrials.gov Identifier: NCT00655941