The major drawback in implementing thrombolytic therapy with streptokinase in cases of acute myocardial infarction (AMI) stems from its antigenicity. To evaluate the dimensions of this problem, the immune response following thrombolytic therapy with streptokinase was prospectively studied in 16 patients with AMI. Streptokinase was given to 12 patients once and to 4 patients twice within 4-14 days. No clinical immune responses were observed following treatment. The specific antistreptokinase immune responses subsequent to streptokinase administration were monitored. The cellular immune response, reflected by the 3H-thymidine uptake of streptokinase-stimulated peripheral blood mononuclear cells, was three times higher than that of the controls. The antistreptokinase circulating IgG antibody level, measured by an enzyme-linked immunosorbent assay, was 8 times higher than that of the controls. No antistreptokinase circulating IgE antibodies could be detected and no decrease in complement concentration was noted. The profile and magnitude of the immune response of patients who had received two treatments were similar to those of patients who had received a single treatment only. Our data suggest that thrombolytic therapy with streptokinase in AMI elicits a characteristic profile of antistreptokinase immune responses, in vitro, not necessarily associated with parallel clinical immune responses. An early repeat treatment with streptokinase was not accompanied by clinical or exacerbated in vitro immune responses.