Background : Recent reports indicate that the isoxazoline compounds have the potential to provide safe and effective treatment of canine generalized demodicosis, a condition that has been traditionally difficult to cure. Controlled field studies are needed to confirm this potential. A study was therefore initiated to investigate the efficacy of a single oral or spot-on treatment with fluralaner, an isoxazoline, compared with multiple topical treatments with imidacloprid-moxidectin, in dogs naturally affected by generalized demodicosis. Methods : Veterinary clinics in 5 European countries enrolled 134 dogs diagnosed with generalized demodicosis. Dogs were randomized to treatment with either fluralaner chewables, fluralaner spot-on, or topical imidacloprid-moxidectin in a 2:2:1 ratio. Both fluralaner formulations were administered once, at the approved dose rate, on day 0. Imidacloprid-moxidectin was administered per label on day 0, and every 4 weeks, more frequently if necessary. At each visit (days 0, 28, 56, 84), dogs were monitored for demodectic mites, using deep skin scrapings, and observed for health and for severity of skin lesions. Treatment was considered efficacious if more than 90% of the dogs were free of live mites at both days 56 and 84. Results : Of 124 dogs completing the study, 57 were diagnosed with juvenile-onset demodicosis and 67 with the adult-onset form. A single treatment with oral or spot-on fluralaner was efficacious, each eliminating mites from at least 98.0% of treated dogs on days 56 and 84. Against juvenile-onset demodicosis, efficacy of the oral and spot-on formulations was 96.0% and 100%, respectively, and against adult-onset demodicosis 100% and 96.7%. Multiple administrations of imidacloprid-moxidectin were not efficacious, eliminating mites from 87.5% of dogs (92.0% with juvenile-onset demodicosis cured; 81.8% with adult-onset demodicosis). All groups showed a marked reduction in skin lesions by day 28, with continuing clinical improvement at each subsequent visit through day 84. There were no treatment-related adverse events. Conclusion : A single administration of fluralaner chewables or fluralaner spot-on is highly effective against juvenile-onset and adult-onset forms of generalized canine demodicosis. Topically applied imidacloprid-moxidectin at weekly to monthly intervals over the 84-day study did not achieve the proportion of mite-free dogs required to demonstrate efficacy.