Homogentisic acid (HGA) spontaneously starts to undergo oxidation and polymerization soon after the beginning of incubation in human blood or plasma at 37-degrees-C, and forms plasma soluble melanins (PSM). Haemolysis accompanies this process in blood. The addition of equimolar quantities of antioxidants delays this oxidation significantly (isoascorbic acid by 2:30-4:00 h; glutathione by 3:20-4:05 h; D-penicillamine by 5:00-5:45 h). HGA is a phenylalanine and tyrosine metabolite, related structurally to the catecholamines and other precursors of melanins. HGA is normally metabolized by the enzyme homogentisic acid oxidase. When this enzyme is genetically missing, part of HGA is excreted in the urine, another part polymerizes darkens many tissues (ochronosis), and produces widespread degenerative changes in cartilage and other connective tissues, joints, blood vessels, heart valves, kidneys and in other tissues. Collectively this disorder is known as alcaptonuria, for which no satisfactory treatment is known. The causes of both alcaptonuric arthritis and rheumatoid arthritis are thought to involve increased oxidative stress. Inflammation of joints and connective tissue damage are involved in both diseases. Oxygen radicals are suspected to cause inflammation and cellular damage. Hydroxyl radicals degrade hyaluronic acid (the viscous synovial fluid of joints). High levels of products of free radical reactions, with fluorescence excitation (ex) and emission (em) maxima in the wavelength ranges of those of PSM (ex 320-400 and em 400-470) were reported in the blood sera and synovial fluids of patients with rheumatoid arthritis. Many chemical reactivities of other melanin precursors (such as the catecholamines, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, catechol) produced in normal metabolic processes are so similar to those of HGA that it seems certain that the unrecognized activities of the other precursors of soluble melanins produce similar degenerative processes in normal aging and particularly in chronic renal failure. Plasma levels of soluble melanins or lipofuscins rise in chronic renal failure and degenerative cardiovascular disease is a major cause of death in chronic renal failure, as in alcaptonuria. The uncommon disorder alcaptonuria, therefore, calls attention to the broadly adverse influence of the soluble melanins and their precursors. These adverse effects are apparently oxidative in nature and emphasize the significance of antioxidant protection in normal human metabolism and in illness and aging.