Objective. To assess the effects of the prescription formulation of glucosamine sulfate (1,500 mg administered once daily) on the symptoms of knee osteoarthritis (OA) during a 6-month treatment course.Methods. Three hundred eighteen patients were enrolled in this randomized, placebo-controlled, doubleblind trial in which acetaminophen, the currently preferred medication for symptomatic treatment of OA, was used as a side comparator. Patients were randomly assigned to receive oral glucosamine sulfate 1,500 mg once daily (n ‫؍‬ 106), acetaminophen 3 gm/day ( n ‫؍‬ 108), or placebo (n ‫؍‬ 104). The primary efficacy outcome measure was the change in the Lequesne index after 6 months. Secondary parameters included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and response according to the Osteoarthritis Research Society International criteria. These outcome measures were assessed using an intentto-treat analysis.Results. At baseline, the study patients had moderately severe OA symptoms (mean Lequesne index ϳ11 points). Glucosamine sulfate was more effective than placebo in improving the Lequesne score, with a final decrease of 3.1 points, versus 1.9 with placebo (difference between glucosamine sulfate and placebo ؊1.2 [95% confidence interval ؊2.3, ؊0.8]) (P ‫؍‬ 0.032). The 2.7-point decrease with acetaminophen was not significantly different from that with placebo (difference ؊0.8 [95% confidence interval ؊1.9, 0.3]) (P ‫؍‬ 0.18). Similar results were observed for the WOMAC. There were more responders to glucosamine sulfate (39.6%) and acetaminophen (33.3%) than to placebo (21.2%) (P ‫؍‬ 0.004 and P ‫؍‬ 0.047, respectively, versus placebo). Safety was good, and was comparable among groups.Conclusion. The findings of this study indicate that glucosamine sulfate at the oral once-daily dosage of 1,500 mg is more effective than placebo in treating knee OA symptoms. Although acetaminophen also had a higher responder rate compared with placebo, it failed to show significant effects on the algofunctional indexes.ClinicalTrials.gov identifier: NCT00110474.