Leflunomide is a disease-modifying anti-rheumatic drug used in the treatment of rheumatoid arthritis due to its anti-inflammatory and immunosuppressive effects. This study aimed to investigate the histological effect of leflunomide on the fundic gastric mucosa of adult male albino rat and the possible ameliorative role of the non-essential amino acid l-arginine. Fifty adult male albino rats were divided randomly into four main groups, group I (control group), group II treated with leflunomide, group III received the L-arginine and group IV received the leflunomide and the l-arginine concomitantly. The four groups were subdivided into two subgroups; the first received the drugs for two weeks and the second received the drugs for four weeks. At the end of the experiment, all rats were sacrificed; the fundic mucosa was dissected out and processed for light and electron microscopic study. Paraffin sections were stained with hematoxylin and eosin, periodic acid Schiff (PAS), Mallory trichrome and immunohistochemically for PCNA antibody. Leflunomide treated (group II) showed sloughing and desquamation of epithelial cells, superficial ulceration, and inflammatory cellular infiltration. Electron microscopic examination revealed absence of apical microvilli and coalescence of secretory granules. L-arginine ameliorated to some extent the histological changes occurred by leflunomide. It can be concluded that leflunomide exerts some histological changes on fundic gastric mucosa and co-administration of l-arginine had ameliorating effects on the histological changes.