Intestinal roundworms infect >2 billion of the poorest peoples and have received little attention. Very little money is spent on much needed drug development for human parasites, making them one of the great neglected tropical diseases. Recently, a new and powerful class of anti-roundworm drugs (anthelmintic) has emerged- crystal proteins (e.g., Cry5B) made by Bacillus thuringiensis (Bt). Here we show that combining Cry5B with nicotinic acetylcholine receptor agonists like tribendimidine and levamisole makes for a potent anti-roundworm cocktail. Roundworms that develop resistance to either class become MORE susceptible to the second class (a phenomenon in the HIV/AIDS field known as hypersusceptibility). The drug classes themselves are synergistic so that you need much less (e.g., 4-10X less) of each in the combination to achieve the same effect as either alone. This means therapy is cheaper and that potential side effects are less of a concern. In general, this combination is predicted to be highly recalcitrant to parasite resistance development.