We studied the efficacy and tolerability of glycosaminoglycan polysulfuric acid (GAGPS) in 80 patients with osteoarthritis (OA) of the knee. Patients received two series of five intra-articular injections, at 1-week intervals, of 25 mg (0.5 ml) GAGPS into the knee in a double-blind, parallel, randomized, placebo-controlled trial. There was an immediate decrease in pain after the injections of 43% with GAGPS and 33% with placebo (P = 0.047) (Jezek pain index). Pain relief of GAGPS vs placebo was not different at other intervals (10, 14, 22, 26 weeks after start of treatment). At 6 weeks the Lequesne index decreased 20% after GAGPS and 9% after placebo (P = 0.17). At 10 weeks the Lequesne index decreased 24% after GAGPS and 13% after placebo (P = 0.20). The decrease in Lequesne index at 14 weeks was 31% after GAGPS and 15% after placebo (P = 0.06). The other measured parameters tended to be more favorably influenced by GAGPS than placebo. GAGPS was well tolerated, with associated mild adverse reactions in 8% of cases. GAGPS may have a role as a symptomatic slow acting drug for OA. Further study appears appropriate.