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Most of the biological and application-oriented studies of synthetic melanins have so far been performed on commercial materials or on dopa melanins with low DHICA content, although it is well known that DHICA is a key constituent of human pigments. Recently, it has been reported that DHICA melanin exhibits potent hydroxyl radical-scavenging properties in the Fenton reaction, whereas DHI melanin does not (Jiang et al., Free Radic. Biol. Med. 2010, 48, 1144–1151). We show now that synthetic DHICA melanin is a highly efficient antioxidant compared to other synthetic eumelanins, proving to be a more efficient scavenger than DHI or dopa melanin in the 1,1-diphenyl- 2-picrylhydrazyl (DPPH), 2,2′-azinobis(3-ethylbenzothiazoline-6- sulfonic acid) (ABTS), and nitric oxide (NO) scavenging assays. Analysis of the optical, paramagnetic and morphological properties of DHICA melanin revealed features far different from those of DHI and dopa melanins. These can be accounted for by prevalent intermolecular interactions compensating for conformationally-hindered p-electron delocalization across the polymer backbone. Thus the somewhat counterintuitive conclusion is that the efficient antioxidant properties of DHICA melanin would be primarily determined by non-planar structures with monomer-like behavior and weak aggregating interactions. Formation of weak aggregates may account moreover for a greater accessibility of free radicals to DHICA compared to compact p- stacked DHI and dopa melanins. These results offer the first chemical explanation as to why Nature selected DHICA to confer (photo)protective properties to skin melanins, a fundamental conundrum of human pigmentation, and provide unprecedented insights to orient the design and to engineer eumelanins with superior antioxidant properties for diverse applications.