Eighty-eight lambs were allocated to one of four groups which were then dosed with 10,000 infective-stage larvae (L3) of one of four populations of Ostertagia circumcincta; the first (S) was an isolate known to be anthelmintic-susceptible; the second (OR) was a multiple anthelmintic-resistant isolate which had been recovered from the field following therapeutic failure of both ivermectin and moxidectin and subsequently maintained in the laboratory without further anthelmintic selection. The third (R) was derived from OR but had been passaged for five generations in the laboratory with each generation being screened with all three broad-spectrum drench families; the fourth (R x S) was an F1 cross between the S and R isolates. On patency, each of the four infection groups was sub-divided into five treatment groups, one of which received no anthelmintic while the others were administered either oral ivermectin (IVM-oral), controlled-release capsules containing ivermectin (IVM-CRCs), oral moxidectin (MOX-oral) or injectable MOX (MOX-inj). Neither formulation of IVM reduced FEC in the R, R x S and OR infected lambs compared to their untreated controls, but significant reductions were observed in all cases following MOX-oral or MOX-inj treatment. Similarly, neither IVM formulation significantly reduced the numbers of R or R x S worms compared to their untreated controls, although the numbers of OR worms were reduced in both cases (P<0.05). Direct comparisons of efficacy across the isolates, however, indicated that neither formulation was any more effective against R x S or OR worms than against the more highly selected R worms. In contrast, both MOX formulations significantly reduced worm numbers of all the resistant isolates compared to their respective untreated controls; furthermore, worm burdens of R x S were reduced significantly more than burdens of R (P<0.05). Reductions in OR burdens, which were intermediate between the two, did not differ significantly from either. The results are consistent with published work on Haemonchus contortus, which suggests that macrocyclic lactone (ML) resistance is expressed as a dominant trait under treatment with IVM. However, these data differ from the H. contortus studies in suggesting that ML resistance in O. circumcincta may effectively be rendered incompletely dominant or recessive by treatment with MOX.