Background: This study was performed to investigate the adverse effects of acute lead intoxication on hemogram, erythrocyte osmotic fragility and oxidant/antioxidant status and the probable ameliorating effect of silymarin in comparison to d-penicillamine.Methods: Forty-eight albino rats were divided in 8 groups and received the following treatments in a 10 day experiment in Shahid Chamran University of Ahvaz, southwest Iran in 2015. Group 1: Normal saline as control; Group 2: 25 mg/kg lead acetate, intraperitoneally (IP) for the last 5 days; Group 3: 100 mg/kg D-penicillamine, IP for the last 5 days; Group 4: 200 mg/kg silymarin, orally for 10 days; Group 5, 6, 7 and 8: In addition to lead, they received D-penicillamine, for the last 5 days, silymarin for 10 days, a combination of silymarin for 10 days and D-penicillamine for the last 5 days, and silymarin for the last 5 days, respectively.Results: Lead exposure induced a significant microcytic anemia accompanied by a significant elevation in total leukocyte, lymphocyte and neutrophil counts. Erythrocyte superoxide dismutase (SOD) and glutathion peroxidase (Gpx) activities were significantly increased along with a significant elevation of malondialdehyde (MDA) concentration in lead treated rats. Activities of SOD and Gpx were significantly alleviated by silymarin administration for 10 days while both Dpenicillamine and silymarin could significantly reduce MDA concentration.Conclusion: Acute lead exposure induced significant leukocytosis and anemia that was associated with increased activity of erythrocyte antioxidant enzymes and lipid peroxidation.Silymarin in contrast to D-penicillamine treatment was more effective in preventing lead-induced oxidative stress in erythrocytes.