This experimental in vivo purpose of this study was to look into the immunomodulatory effects of purified staphylokinase produced by local clinical Staphylococcus aureus isolates compared with streptokinase which is used as a thrombolytic agent. All mice (40) injected intramuscularly (i.m.) with different concentrations of the purified lyophilized staphylokinase and streptokinase for 12 days, and immunized with 10% SRBCs (i.p) on day 4 and 8 of the schedule, and Staphylococcus aureus suspension and normal saline for positive and negative control groups. Focus on the estimation of Arthus and delayed-type hypersensitivity with the absolute neutrophil count, measurement of antibody titter by Hemagglutination, and detecting serum concentration of cytokines (IL4 -IL10 -IL 17) and TLR-2 by using sandwich ELISA. The statistical analysis found a significant difference (P ≤ 0.01) between staphylokinase and streptokinase treated groups and control groups (positive and negative). The data showed an increase in cytokine levels in treated groups compared with control groups. Observed in A2 (4µg staphylokinase) and B2 (4µg streptokinase)groups, also significant elevation (P ≤ 0.01) of IL-10 level in all groups as compared to positive and negative control groups but the highest value was observed in A3 (8µg) and B3 (8µg) group. In conclusion, the staphylokinase is better than streptokinase because of the increasing level of IL-10 and less appearance of hypersensitivity, so decline in IL-4 and its small size, in addition, to act as an immunomodulator that indicates the possibility to use in the treatment of thrombosis.