In this study, we examined the effects of natural humic acid (HA) purified from drinking well-water in Blackfoot disease (BFD) endemic areas, using synthetic humic acid (SHA), such as protocatechuic acid, ferulic acid, vanillic acid or catechol, and trivalent arsenic on human plasmin activity. Data in this report indicated that both HA and SHA inhibited human plasmin activity by 20-80 and 5-95%, respectively, at concentrations of 20-480 microg/ml. Organometallic complexes composed of HA and arsenic show enhanced inhibition of plasmin activity as compared with either HA or arsenic alone. Monomers of HA or arsenic alone do not inhibit plasma activity. Oxidative stress may play a role in the inhibition of plasma activity, as various free-radical scavengers, such as ascorbic acid, alpha-tocopherol, catalase and superoxide dismutase (SOD), abrogate the inhibitory effects of HA and HA-arsenic complexes. The notion that HA/organometallic complexes (HA/OR) impaired plasmin activity was significant, due to the fact that both of these agents (HA and arsenic) are etiological factors in the development of peripheral vascular diseases, such as BFD. This report substantiates the inhibitory effects of HA/OR on plasmin activity, and thus provides evidence for the partial mechanism of action of HA/OR in BFD.