Ivermectin (IVM) and moxidectin (MXD) are broad-spectrum endectocides belonging to the avermectin/milbemycin class of antiparasitic drugs not approved for use in dairy sheep. However, these compounds are widely used extra-label to control endo- and ecto-parasites in lactating dairy sheep. Effects of the route of administration on the pattern of IVM and MXD excretion in milk were comparatively characterized in lactating dairy sheep. The relationship between the milk and plasma disposition kinetics after subcutaneous (s.c.) and oral administration at 200 microg/kg body weight was also evaluated. IVM and MXD concentration profiles were measured in milk and plasma using a specific HPLC-based methodology. IVM and MXD were extensively distributed from the bloodstream to the mammary gland and large quantities, particularly for MXD, were excreted in milk. Residual concentrations of IVM were recovered in milk up to 11 d (oral treatment) or 25 d (s.c. treatment) post treatment. However, high MXD concentrations were detected in milk between 1 h and 35 d after its oral and subcutaneous administration. MXD concentrations as high as 3.77 ng/ml (oral) and 30.3 ng/ml (s.c.) were measured in milk at day 35 post administration. A higher MXD excretion in milk, compared with that of IVM, was obtained for both administration routes. An extensive plasma to milk distribution pattern was observed, being the area under the concentration-time curve of MXD obtained in milk up to 14-fold higher than that measured in the bloodstream. The total fraction of the administered dose excreted in milk for MXD was significantly higher than that for IVM, which agrees with the well known higher MXD lipophilicity. The long persistence of milk residual concentrations of MXD and IVM in lactating dairy sheep should be seriously considered before their extra-label use is recommended.