Patients with osteoarthritis (OA) of the knee were treated with chondroitin sulfate (CS, Condrosulf, IBSA, Lugano, CH) in a randomized, double-blind, placebo-controlled study, performed in two centres. The efficacy and tolerability of oral CS capsules 2 x 400 mg/day vs placebo was assessed in a 6-month study period. Patients with idiopathic or clinically symptomatic knee OA, with Kellgren and Lawrence radiological scores I-III, were included in this trial. Clinical controls were performed at months 0, 1, 3 and 6. Eighty patients completed the 6-month treatment period. Lequesne's Index and spontaneous joint pain (VAS) decreased constantly in the CS group; on the contrary, slight variations of the scores were reported in the placebo group. The walking time, defined as the minimum time to perform a 20-meter walk, showed a statistically significant constant reduction only in the CS group. ANOVA with repeated measures showed a statistically significant difference in favor of the CS group for these three parameters. During the study, patients belonging to the placebo group reported a higher paracetamol consumption, but this consumption was not statistically different between the two treatment groups. Efficacy judgements were significant in favor of the CS group. Both treatments were very well tolerated. All these results strongly suggest that chondroitin sulfate acts as a symptomatic slow-acting drug in knee OA.