To determine if the dietary supplements, glucosamine and/or chondroitin, result in reduced joint space narrowing (JSN) and pain among people with symptomatic knee osteoarthritis. A double-blind randomised placebo-controlled clinical trial with 2-year follow-up. 605 participants, aged 45-75 years, reporting chronic knee pain and with evidence of medial tibio-femoral compartment narrowing (but retaining >2 mm medial joint space width) were randomised to once daily: glucosamine sulfate 1500 mg (n=152), chondroitin sulfate 800 mg (n=151), both dietary supplements (n=151) or matching placebo capsules (n=151). JSN (mm) over 2 years was measured from digitised knee radiographs. Maximum knee pain (0-10) was self-reported in a participant diary for 7 days every 2 months over 1 year. After adjusting for factors associated with structural disease progression (gender, body mass index (BMI), baseline structural disease severity and Heberden's nodes), allocation to the dietary supplement combination (glucosamine-chondroitin) resulted in a statistically significant (p=0.046) reduction of 2-year JSN compared to placebo: mean difference 0.10 mm (95% CI 0.002 mm to 0.20 mm); no significant structural effect for the single treatment allocations was detected. All four allocation groups demonstrated reduced knee pain over the first year, but no significant between-group differences (p=0.93) were detected. 34 (6%) participants reported possibly-related adverse medical events over the 2-year follow-up period. Allocation to the glucosamine-chondroitin combination resulted in a statistically significant reduction in JSN at 2 years. While all allocation groups demonstrated reduced knee pain over the study period, none of the treatment allocation groups demonstrated significant symptomatic benefit above placebo. NCT00513422; http://www.clinicaltrials.gov.