Objectives. Cyclosporine A (CsA) is used for the treatment of autoimmune and inflammatory disorders. However, CsA-induced nephrotoxicity remains an important clinical problem, and oxidative stress has been implicated as a possible responsible mechanism. We assessed the protective ability of N-acetylcysteine (NAC), an antioxidant, against CsA-induced nephrotoxicity. Materials and Methods. Wistar albino rats were randomly assigned into four groups. Group I rats were treated with sodium chloride as control, group 2 with CsA, group 3 with CsA and NAC, and group 4 with NAC alone. Animals were sacrificed and blood samples were analyzed for blood urea nitrogen (BUN), serum creatinine (Cr), malondialdehyde (MDA) and nitric oxide (NO) levels, and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. Kidney sections were analyzed for MDA and NO levels and SOD and GSH-Px activities, as well as histopathological changes. Results. Overall, the treatment of rats with CsA alone produced significant increases in NO and MDA levels and significant decreases in SOD and GSH-Px activities in serum and renal samples. Morphological changes, including tubular epithelial atrophy, vacuolizations, and cellular desquamations, were clearly observed in the rats treated with CsA alone. Concurrent NAC administration with CsA improved renal function, as indicated by lower BUN and Cr values. Moreover, NAC significantly reduced MAD and NO levels and increased SOD and GSH-Px activities in serum and renal tissue, as well as provided a histologically proven protection against CsA-induced nephrotoxicity. Conclusion. These results indicate that NAC produces a protective mechanism against CsA-induced nephrotoxicity and suggest a role for oxidative stress in pathogenesis.