Wuchereria bancrofti, Brugia malayi, and B. timori, are filarial nematodes that cause lymphatic filariasis, an extremely debilitating disease, which is prevalent in the developing world. Current control is based on mass drug administration with annual doses, under a two-drug regimen. One of these drugs, ivermectin, has been considered a wonder drug since its discovery, but its mode of action in filarial nematodes is still unclear. Currently, ivermectin is thought to decrease helminth-immunomodulation by inhibiting protein secretion from the excretory/secretory pore. We performed in vitro motility assays, neutrophil attachment assays, and neutrophil activation assays, which suggest a role for the immune system, in conjunction with ivermectin, in clearing microfilariae from blood circulation. Also, transcriptomic analysis of microfilariae treated with ivermectin, in vivo, reveals gene regulation that could indicate a mode of action in filarial nematodes. Due to increasing resistance it is imperative to understand ivermectins mode of action.