The aim of this prospective, randomized, single-blinded, and placebo-controlled clinical trial was to investigate the efficacy of a moxidectin pour-on solution for the treatment of Chorioptes bovis infestation in Belgian draft horses, and in addition, to evaluate the effect of this treatment on the clinical signs and lesions associated with chronic progressive lymphedema (CPL). Nineteen privately owned Belgian draft horses were randomly assigned to either a treatment group (moxidectin pour-on formulation, n = 10) or a placebo group (phosphate-buffered saline (PBS), n = 9). On Day 0, all 19 horses tested positive for the presence of C. bovis in superficial skin scrapings. Prior to treatment, all feathering on the distal limbs of the horses was clipped. Treatment was applied twice (Day 0 and 7). Pour-on moxidectin (Cydectin 0.5% Pour-On; Zoetis) was evenly distributed over the distal legs of the horses at a dose of 1.5 mg moxidectin/kg body weight. Animals in the placebo group were treated with PBS. Pretreatment and follow-up examinations consisted of counting living mites in superficial skin scrapings, scoring pruritus, and scoring mange-associated and CPL-associated lesions (skinfold score and skin lesion score). Horses in the placebo group and moxidectin group were followed up to 8 weeks and 24 weeks after the first treatment, respectively. On Day 14, no living mites were found in any of the horses in the moxidectin group (p = 0.013). These horses continued to remain free of mites, until the final sampling conducted at 24 weeks following the initial application of moxidectin, when three horses again showed living mites in skin scrapings. Treatment with moxidectin resulted in a significant reduction of both CPL-associated skin lesion scores (p = 0.003) and pruritus scores (p = 0.001) after only seven days. By Day 56, still no signs of pruritus (p < 0.0001) were detected, with significant improvement of mange-associated lesions (p < 0.0001). Although the skinfold score did not show a significant reduction ...