AbstractPrurigo is a common skin disease characterised by erythematous macules and papules/nodules with severe pruritus. We report here two cases with treatment‐resistant prurigo that were successfully treated with duloxetine hydrochloride, a serotonin–norepinephrine reuptake inhibitor. In vivo experiments with a mouse model of prurigo‐like inflammation showed that duloxetine hydrochloride ameliorated not only scratching behaviours, but also skin inflammation. Duloxetine hydrochloride appears to be useful for treating prurigo via modulating itch signals and immune responses.