Glucosamine sulfate (Dona , CAS 29031-19-4) is a drug used in the treatment of osteoarthritis. when orally given, it is more effective than placebo and at least as effective as non-steroidal anti-inflammatory drugs in relieving osteoarthritis symptoms. The aim of this multicenter, randomised, placebo-controlled, double-blind, parallel-group study was to assess the efficacy and safety of glucosamine sulfate intramuscularly given on the same parameters. 155 out-patients with knee osteoarthritis (Lequesne's criteria), radiological stave between I and III, Lequesne's severity index of at least 4 points and symptoms for at least six months, were treated with i.m. glucosamine sulfate (or placebo) 400 mg twice a week for 6 weeks. Clinic visits were performed at enrollment, after a 2-week baseline, at weekly intervals during treatment and 2 weeks after drug discontinuation. Responders to treatment were considered those patients with a reduction of at least 3 points in the Lequesne index, together with a positiveoverall judgment by the investigator. The Lequesne index was slightly over 10 points in average in both groups at the beginning of treatment. A significant decrease in the index was observed for glucosamine compared to placebo (3.3 vs. 2.0 points in average, respectively; p<0.05, Student's t-test). The responder rate in the evaluable patients was 55% with glucosamine (n=73) and only 33% (n=69) with placebo (p=0.012), Fisher's Exact Test). According to the intention-to-treat approach, considering also drop-outs, these proportions were 51% vs. 30% (p=0.015). both local and systemic tolerability of i.m. glucosamine sulfate were good and without difference in comparison with placebo. The results of this study showed that i.m. glucosamine sulfate induced a significant improvement on the symptoms of knee osteoarthritis (pain and motion limitation), over a 6-week therapeutic course. The improvement steadily developed throughout treatment and reached a statistically significant difference in comparison with lacebo. The most impressive decrease in pain and functional limitation severity score started to be evident after the 3rd and was achieved between the 4th and 5th week of treatment. Other referenced studies showed that oral glucosamine sulfate yielded an even faster trend for improvement in osteoarthritis symptoms (2-3 weeks in average). This suggests that a promising therapeutic option may be represented by the combination of the oral and the i.m. administration routes during the initial weeks of treatment. In conclusion, the results of this study with intramuscular glucosamine sulfate confirm the positive effects obtained with the oral preparation of the drug on pain relief and functional improvement in knee osteoarthritis patients. Glucosamine sulfate is therefore a candidate as a symptomatic Slow Acting Drug in Osteoarthritis according the recent definition by ILAR, in that it selectively relieves osteoarthritis symptoms, with a few week delay in the onset of its action which is then sustained throuhout treatment and tends to last after drug discontinuation. Based on these and other results, a suggestion is made that the parenteral, i.m., administration could usefully complement the oral one.