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We studied the short‐term effects of a single dose of 150 g/kg body weight ivermectin on Mansonella streptocerca in an area endemic for streptocerciasis, but not for onchocerciasis, in western Uganda. Six and 12 days after treatment no microfilariae (mf) were found in the skin of 53 out of 96 mf carriers living in 3 villages, and the geometric means of the mf densities of remaining mf carriers were only 33–40% of pretreatment levels. This reduction of mf density was highly significant (P<0.0001). Immunohistological examination of skin biopsies showed degenerated and disintegrating mf surrounded by activated eosinophils (positive for activated cationic protein), macrophages, and neutrophils (positive for myeloperoxidase and defensin) on day 6 after treatment. Remarkable was the invasion of young, L1 protein‐positive macrophages and the release of neutrophil defensin as signs of acute inflammation. We conclude that ivermectin has a strong microfilaricidal activity against M. streptocercaCommon adverse effects were increased pruritus and acute papular dermatitis in 45% of 86 mf carriers on day 6 after treatment. No serious adverse side‐effects were noticed in about 700 treated persons.