Background: Treatment with aqueous extract of Calotropis Procera was examined only for short periods. So, The present study was designed to examine the influences of long term administrations of aqueous extract of Calotropis Procera on male and female rabbits. Material and methods: The extract was daily oral administered to thirty adult rabbits divided into two sets each set contain 3 groups (5/each) for a period of 8 weeks. The doses administered were 80 and 40 mg/kg body weight as high and low doses for both male and female test groups. Percentage of body weight change, serum biochemistry (Alanine amino transferases (ALAT), aspartate amino transferases (ASAT) , Alkaline phosphatase, total protein, albumin, globulin, A/G ratio, urea and creatininre), hematological parameters (PCV, WBCs, RBCs, Plateletsand Hb) and the blood indices (M.C.V., M.C.H. and M.C.H.C.) were examined. Results: Results showed that there was no mortality or clinical signs observed among the treatment and the control groups. No significant changes in the percentage of body weight gain, hematological parameters, blood indices has been noticed in all treated groups Highly significant decreases in serum total protein and albumin in male and female rabbits has been recorded at high doses. While the globulin and A/G ratio revealed no significant changes. Serum ASAT , urea and creatinine levels were highly significant increases (P >0.01) and the activity of ALAT and ALP was significant increases (P >0.05) in male and female rabbits at high doses only. Conclusions: Some toxicological effects were observed after administration of aqueous leaves extract of Calotropis Procera at high doses in the long term for male and females rabbits