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A single administration of complete Freund's adjuvant (CFA), type 1 carrageenan (Car), or silica 7, 2, and 2 days, respectively, before infection with a low dose (1 × 102 plaque-forming units/mouse) of encephalomyocarditis D (EMC-D) virus resulted in a significant increase in the incidence of diabetes in SJL/J mice (100%) compared with untreated EMC-D virus–infected mice (40%). Peritoneal macrophages were isolated from uninfected SJL/J mice, which had been treated once with silica, and transferred into SJL/J mice 2 days before low-dose EMC-D infection. Approximately 90% of the mice became diabetic, whereas 30% of mice that received virus alone became diabetic. The depletion of macrophages by treatment with the combined anti-Mac-1 and anti-Mac-2 monoclonal antibodies after a single administration of CFA, Car, or silica resulted in almost complete prevention of β-cell destruction in EMC-D virus–infected mice. Furthermore, none of the mice in which macrophages were depleted by long-term treatment with silica and 10% of the mice treated with Car before virus infection became diabetic. On the basis of these observations, we conclude that macrophages are directly involved in the destruction of β-cells, leading to the development of clinical diabetes in EMC-D virus–infected mice.