Objective. To evaluate the symptomatic effects of highly purified chondroitin 4 and chondroitin 6 sulfate (CS) therapy in patients with osteoarthritis (OA) of the hand.Methods. This investigator-initiated, singlecenter, randomized, double-blind, placebo-controlled clinical trial included 162 symptomatic patients with radiographic evidence of hand OA (American College of Rheumatology criteria). Inclusion criteria included patient's assessment of global spontaneous hand pain of at least 40 mm on a 0-100-mm visual analog scale (VAS) and functional impairment of at least 6 (0-30 scale) on the Functional Index for Hand OA (FIHOA) in the most symptomatic hand. Patients received either 800 mg of CS (n ‫؍‬ 80 patients) or placebo (n ‫؍‬ 82 patients) once daily for 6 months and were analyzed in an intent-totreat approach. The two primary outcomes were the change in the patient's assessment of global spontaneous hand pain and in hand function (by FIHOA score) from baseline to month 6. Secondary outcomes were improvement in grip strength, duration of morning stiffness, acetaminophen consumption, and the investigator's global impression of treatment efficacy.Results. There was a significantly more pronounced decrease in the patient's global assessment of hand pain in the CS group than in the placebo group (difference VAS scores ؊8.7 mm; P ‫؍‬ 0.016). Hand function improved significantly more in the CS group than in the placebo group (difference in FIHOA scores ؊2.14; P ‫؍‬ 0.008). There was a statistically significant between-group difference in favor of CS for the duration of morning stiffness and for the investigator's global impression of treatment efficacy. Changes in grip strength, acetaminophen consumption, and safety end points were not significantly different between the two groups.Conclusion. This study demonstrates that CS improves hand pain and function in patients with symptomatic OA of the hand and shows a good safety profile.Osteoarthritis (OA) is a degenerative disorder that primarily affects the articular cartilage and causes painful disease flares and disability in activities of daily living. In developed countries, OA is the most common form of arthritis, resulting in a significant impact on medical expenses, both in terms of direct and indirect medical costs (1). Hand OA is present in ϳ20-30% of adults (2,3), with age-related increases, reaching a prevalence of Ͼ50% after the age of 60 years (4,5). The most frequently affected joints are the distal interphalangeal (DIP), proximal interphalangeal (PIP), thumb interphalangeal, and trapeziometacarpal joints (6).Despite its high prevalence and its impact on quality of life (7), the therapeutic options in hand OA are still limited. Clinical trials examining the efficacy of therapeutic approaches to hand OA specifically are scarce (8-10). Thus, management of hand OA has been ClinicalTrial.gov identifier: NCT00291499.