The horse milk gains increasing interest as a food product for sensitive consumers, such as children with food allergies or elderly people. We investigated the plasma and milk disposition, faecal excretion and efficacy of per os ivermectin (IVM) and pour-on eprinomectin (EPM) in horses. Ten mares were divided into two groups. The equine paste formulation of IVM and bovine pour-on formulation of EPM were administered orally and topically at dosage of 0.2 and 0.5 mg/kg bodyweight. Blood, milk and faecal samples were analysed using high-performance liquid chromatography. The plasma concentration and persistence of IVM were significantly greater and longer compared with those of EPM. Surprisingly, EPM displayed a much higher disposition rate into milk (AUC(milk/plasma): 0.48) than IVM (AUC(milk/plasma): 0.19). IVM exhibited significantly higher faecal excretion (AUC(faeces): 7148.54 ng.d/g) but shorter faecal persistence (MRTfaeces: 1.17 days) compared with EPM (AUC(faeces): 42.43 ng.d/g and MRTfaeces: 3.29 days). Faecal strongyle egg counts (EPG) were performed before and at weekly intervals after treatment. IVM reduced the EPG by 96-100% for up to 8 weeks, whereas the reduction in the EPM group varied from 78 to 99%. In conclusion, due to the relatively low excretion in milk, EPM and IVM may be used safely in lactating mares if their milk is used for human consumption. Nevertheless, much lower plasma and faecal availabilities of EPM could result in subtherapeutic concentrations, which may increase the risk of drug resistance in nematodes after pour-on EPM administration compared with per os IVM.