Introduction: Glucosamine (GA), chondroitine sulfate (CS) and methyl-sulfonyl-methane (MSM) are among the most widely used dietary supplements for treatment of osteoarthritis. In the present study, histopathological alterations and their therapeutic effects, in high doses, were evaluated in monoiodoacetat (MIA)-induced osteoarthritis (OA) in Femorotibial joint of rat.Materials & Methods: To induce OA, single dose of MIA (1mg/knee) and saline were injected intra-articularly to the left and right knee joint of rat, respectively. Then, the beneficial effects of food supplements were studied in different groups, orally; Group 1: administration of GA (750 mg/kg), Group 2: administration of GA+CS (750+500 mg/kg), Group 3: administration of GA+MSM (750+200 mg/kg), Group 4: administration of GA+CS+MSM (750+500+200 mg/kg). Histopathological changes in knee joints were studied after two weeks.Results: Administration of GA alone, in OA knee, significantly prevented damage induced by MIA to chondrocytes and proteoglycane (PG) (p<0.01). No inflammatory cells or cell proliferation in synovial were observed, either. Additional supplements such as CS and/ or MSM did not produce more protective effects on chondrocytes or PG. Conclusion: It is concluded that in short term treatment with food supplements, GA plays the major role in protection of the articular cartilage besides the anti-inflammatory effects. More research is needed perhaps, using different doses or in longer period (without manufacturers interference) to guide us the correct usage of these dietary supplements.