The objective of this work was to study the safety of combined therapy of leflunomide and celecoxib. Male albino rats were used. They were divided into 3 main groups, each was further subdivided into 4 subgroups. Rats were treated with celecoxib, leflunomide or combination of both orally for 6 weeks in a dose of 10 mg/kg for each drug. The first main group was left under normal laboratory conditions. Rats of the second main group were exposed to stress. Rats of the third main group were exposed to coronary artery ligation. Macroscopic gastric ulcer score was calculated for the first and second main groups. Also, histopathological examination of stomach, liver, heart and kidney was done. Planimetry of histological heart sections of the third main group stained with HBFP was done. The percentage of the infarction area was calculated. In addition, ECG was recorded. In this study , celecoxib and leflunomide resulted in significant gastric erosion. Also, both drugs caused significant increase in the area of infarction. Leflunomide caused hydropic changes (that exaggerated with combined therapy), steatosis and spotty necrosis of the liver cells. We concluded that the combination of both drugs had a synergistic harmful effect on the stomach, the heart and the liver. This combination should be avoided specially in RA patients whom have higher risks for gastric and cardiac diseases.