The macrocyclic lactones are the only anthelmintics used to prevent heartworm disease, but it is very difficult to reproduce their in vivo efficacy against Dirofilaria immitis larvae in experiments in vitro. These assays typically measure motility, suggesting that paralysis is not the mode of action of the macrocyclic lactones against D. immitis. We isolated peripheral blood mononuclear cells (PBMC) and neutrophils from uninfected dogs and measured their adherence to D. immitis microfilariae (Mf) in the presence of varying concentrations of ivermectin. We found that adherence of PBMC to the Mf was increased in the presence of ivermectin concentrations ≥100nM and adherence of neutrophils was increased in drug concentrations ≥10nM. Up to 50% of Mf had adherent PBMC in the presence of the drug, and binding was maximal after 40h incubation. Neutrophil adherence was maximal after 16h, with about 20% of the Mf having at least one cell adhered to them. Adherent neutrophils showed morphological evidence of activation. These results are consistent with a model in which the macrocyclic lactones interfere with the parasites ability to evade the host's innate immune system.