Abstract: The present study was conducted to investigate the effects of eicosapentaenoic acid on glucocorticoid-induced bone changes in rats, and to compare them with those of alendronate. Thirty six male Wistar rats, 2.5 months of age, were divided into six groups (n = 6 each) and treated with 0.9% NaCl (control), methylprednisolone 7 mg/kg, once a week subcutaneously, methylprednisolone + alendronate 20 µg/kg, twice a week subcutaneously and methylprednisolone + 80 or 160 or 320 mg/kg eicosapentaenoic acid, per day orally, for 6 weeks. At the end of the experiment, serum and urinary parameters of bone metabolism determined and bone histomorphometric analyses performed on cancellous bone of femoral epiphysis and metaphysis and cortical bone of tibial diaphysis. There were no significant differences in serum and urinary parameters among groups. Decrease of epiphyseal and metaphyseal trabecular width, epiphyseal bone area/tissue area and increase of epiphyseal trabecular separation observed in the methylprednisolone group compared to control. Alendronate restored all of these parameters except metaphyseal trabecular width, which increased significantly by eicosapentaenoic acid at the doses of 80 and 160 mg/kg. Effects of alendronate and 160 mg/kg eicosapentaenoic acid on bone area/tissue area, alendronate and eicosapentaenoic acid at the doses of 80 and 160 mg/kg on trabecular separation and alendronate and eicosapentaenoic acid at doses of 160 and 320 mg/kg on epiphyseal trabecular width were statistically similar. Methylprednisolone did not significantly change cortical bone parameters including cortical width and marrow area/cortical area. Eicosapentaenoic acid, especially, at the dose of 160 mg/kg exerts beneficial effects on methylprednisolone-induced bone changes in rats; these effects are similar or sometimes even better than alendronate.