Significance The etiology of Huntington disease (HD), a progressive neurodegenerative disorder caused by polyglutamine (polyQ) expansion in huntingtin, is not well clarified. Here using a Drosophila model of HD, we show that altered expression of genes involved in copper metabolism can significantly modulate the HD progression. Dietary copper intervention also modifies HD phenotypes in the fly. Copper reduction dramatically decreases the level of toxic huntingtin levels. Strikingly, substitution of two potential copper-binding residues of huntingtin completely dissociates the copper-intensifying toxicity of huntingtin. Our results therefore indicate huntingtin entails both the copper-facilitated toxicity as conferred by direct copper binding and the copper-independent polyQ toxicity and suggest that an ideal HD therapy would need to take both of these actions into consideration.