Objective. To assess the efficacy and safety of combination therapy with chondroitin sulfate (CS) and glucosamine sulfate (GS) compared to placebo in patients with symptomatic knee osteoarthritis (OA). Methods. A multicenter, randomized, double-blind, placebo-controlled study was performed in 164 patients with Kellgren/Lawrence grade 2 or grade 3 radiographic knee OA and moderate-to-severe knee pain (meanSD global pain score 62.111.3 mm on a 100-mm visual analog scale [VAS]). Patients were randomized to receive either combined treatment with CS (1,200 mg) plus GS (1,500 mg) or placebo in a single oral daily dose for 6 months. The mean change from baseline in the VAS global pain score was set as the primary end point. Secondary outcomes included the mean change in the investigator's global assessment of disease activity, total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), pain and function subscale scores on the WOMAC, responder rates based on the Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) 2004 response criteria, and rescue medication use. Adverse events were also recorded. A Data and Safety Monitoring Board was instituted to ensure patient safety and data accuracy. Results. Intriguingly, in the modified intent-to-treat (mITT) population, CS/GS combination therapy was inferior to placebo in the reduction of joint pain (mean +/- SD change in VAS global pain score over 6 months -11.8 +/- 2.4 mm [19% reduction] in patients receiving CS plus GS versus -20.5 +/- 2.4 mm [33% reduction] in patients receiving placebo; peak between-group difference in global pain score at 6 months 8.7 mm [14.2%], P<0.03), but no between-group differences were seen in the per-protocol completers. Both placebo treatment and CS/GS combination treatment improved to a similar extent the total WOMAC score as well as the pain and function WOMAC subscale scores, both in the mITT population and in the per-protocol completers. Neither the OMERACT-OARSI responder rate nor the frequency of rescue medication use differed between the treatment groups. Severe adverse events were uncommon and equally distributed. Conclusion. The results of this trial demonstrate a lack of superiority of CS/GS combination therapy over placebo in terms of reducing joint pain and functional impairment in patients with symptomatic knee OA over 6 months. Further research might fully elucidate the suitability of CS/GS combination therapy in patients with OA.