The decoction of the stem bark of Salix alba (EASA) is traditionally used in Iran against headache, low back pain and to treat piles. The present investigation was carried out to evaluate the safety of decoction of Salix alba stem bark extract after acute and sub-chronic oral administration in male rodents. For the acute study, a single administration of (EASA) was given orally to male mice at doses of 2 ,4, 8, 12,16 and 20 g/kg. In the sub-chronic toxicity study, Salix alba bark extract was administered orally as a single administration to male Wistar rats at doses of 200, 400, 800 and 1600 mg/kg/day for 28 days. Animal body weight was recorded throughout the experimental period while hematological and biochemical parameters of blood and urine, as well as the weight of organs, were evaluated. The relative weight of organs was affected significantly by the treatment at the doses of 800 and 1600 mg/kg between liver and kidney that was dose-related. Hematological changes were observed at the doses 400, 800 and 1600 mg/kg at the parameters of RBC, Hgb, HCT, PLT, and WBC. Serum AST, ALT, ALP, and total bilirubin increased significantly while total protein and triglycerides significantly decreased. Renal function indices assay in blood showed a significant modification in the 800 and 1600 mg/kg groups at the parameters of creatinine, uric acid and potassium compared to control while, in urine, protein, and calcium markedly increased at the doses of 1600 mg/kg. These results showed that there is a wide margin of safety for the therapeutic use of EASA and that the aqueous stem bark extract of Salix alba had no toxicity in oral acute high dose administration and very low toxicity in oral sub-chronic administration.