The antihypertensive drug, captopril, exerted an anticoagulant effect upon clotting time as followed by prothrombin time (PT) and activated partial thromboplastin time (APTT), with prolongation of clotting observed at 4.25 × 10−3 M and 4 × 10−3 M captopril for PT and APTT, respectively, using commercial level I plasma. Utilizing level III plasmas, PT and APTT values were both prolonged by 4.25 × 10−3 M captopril. Captopril (6 × 10−3 M) also directly prolonged the clotting of thrombin in a thrombin-factor II-deficient plasma assay, whereas 5 × 10−3 M captopril inhibited FIIDP in a thrombin-FIIDP assay. In thrombin-fibrinogen assays, pre-incubation of 2.5 × 10−3 M captopril with fibrinogen also prolonged clotting time, whereas 3 × 10−3 M captopril prolonged thrombin activity. These data suggest that thiol-disulfide exchange permits reduction of disulfide groups in thrombin and fibrinogen, altering their tertiary structure and physiological function. Lisinopril at a pharmacological 10−2 M also prolonged APTT, although it lacks a thiol group. Polylysine (1k-4k) affected a prolongation of APTT at 6.7 × 10−6 M, suggesting inhibition of clotting by a different mechanism.