Resistance could lead to breakouts of the infection in communities where it has been brought under control, a Canadian study in the Lancet reports.
Ivermectin, used since the late 1980s, is the only drug available for the mass treatment of river blindness.
Experts warned the findings highlighted the urgent need for new treatments.
River blindness (onchocerciasis) is caused by a nematode worm which is transmitted by a black fly.
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