A young male giraffe (Giraffa camelopardalis) recently acquired by the Lion Country Safari in Loxahatchee, Florida, was diagnosed and successfully treated for Haemonchus infection while in quarantine. Seven weeks after introduction into a group of resident giraffes, this giraffe presented with diarrhea. Fecal evaluation revealed an extremely high count of 16,700 eggs /g, with larval identification of the parasite as Haemonchus. A larval development assay showed resistance to the three classes of anthelmintics currently used to treat Haemonchus contortus: the benzimidazoles, imidazothiazoles, and macrocyclic lactones. The giraffe was treated with a combination of moxidectin topically and fenbendazole orally, and follow-up fecal examination 2 wk later showed a marked reduction in strongyle-type eggs. However, within 2 mo the giraffe had a packed cell volume of 22% and an eggs per gram count of 11,900. The animal was then treated with moxidectin topically and copper oxide wire particles orally and removed from the contaminated area. Because of the unusual host, molecular analysis of the parasite was employed, which confirmed the nematode as H. contortus. It is likely that the monthly rotational deworming schedule first implemented more than 5 yr earlier contributed to the development of multiple anthelmintic resistance in this H. contortus population. The proper use of anthelmintics and good pasture management are crucial to reducing the parasite burden in captive giraffe.