We studied the capacities of naked and proteincoated monosodium urate (MSU) crystals to stimulate superoxide anion (O2) release by human polymorphonuclear leukocytes (PMN). Uncoated MSU stimulated significant O2 production by cytochalasin B-treated PMN. Precoating MSU with IgG caused an increase in mean O2 production, whereas precoating heated MSU with serum or plasma inhibited O2 release. Unheated MSU crystals, which activate complement to a greater extent than heated crystals, also provoked O2 generation, an effect again abrogated by precoating with serum but not with plasma. Coincubation of unheated MSU and plasma resulted in an enhancement of O2 generation. The results of these experiments support the hypothesis that adsorbed proteins modulate the phlogistic potential of MSU and that the surface activation of humoral mediators contributes to the local inflammatory response.