The inflammatory response in endogenous uveitis or after anterior segment surgery was noted to be substantially greater in heavily pigmented eyes. Because varying amounts of melanin are released into the anterior chamber after intraocular inflammation, it was hypothesized that a proinflammatory effect of melanin might account for the enhanced inflammatory response in these eyes. To test this hypothesis, albino (BALB/c) or pigmented (C57BL/6) mice were challenged in the anterior chamber 2 weeks after a subcutaneous foot pad injection of horse serum or conalbumin dissolved in Freund's complete adjuvant. The degree of inflammation in the challenged eyes was determined by histologic examination 72 hr after the challenge. In all cases, the inflammatory infiltrate consisted mainly of polymorphonuclear leukocytes suggestive of an Arthus reaction. An anterior chamber challenge of horse serum-sensitized BALB/c or C57BL/6 mice with horse serum alone resulted in mild inflammation, which was augmented markedly by challenge with a combination of horse serum and melanin. The presence of melanin in the anterior chamber similarly increased the inflammatory response of conalbumin-sensitized mice to anterior chamber challenge with conalbumin. Melanin in the anterior chamber also significantly (P less than 0.05) augmented the inflammatory response of conalbumin-sensitized mice to a horse serum challenge, but it did not significantly augment the inflammatory response of horse serum-sensitized mice to a conalbumin challenge. The heterologous antigens induced minimal inflammation in the absence of melanin. Injection of melanin alone did not evoke an inflammatory response. Ocular challenge with melanin alone or in combination with antigen induced minimal inflammation in nonsensitized mice. However, preincubation of melanin with sera from horse serum-sensitized mice significantly increased its proinflammatory capacity when injected with horse serum into the anterior chamber of nonsensitized mice. In vitro binding studies using fluorescein isothiocyanate-conjugated mouse immunoglobulin G showed a high binding capacity of melanin for immunoglobulin G. It was concluded that the presence of free melanin in the anterior chamber can increase intraocular inflammation. Although the mechanism(s) by which melanin augments inflammation has not been defined, these data suggest that the binding of serum components (such as antibodies) to melanin may contribute to its proinflammatory effect.