Pruritus associated with malignancy may be one of the most bothersome symptoms in advanced cancer. Its control is still difficult to achieve and is a challenge to palliative medicine specialists. We describe five patients suffering from pruritus of different etiologies who responded rapidly to administration of paroxetine, a serotonin reuptake inhibitor, in a dose-dependent manner. Two patients experienced transient but severe nausea and vomiting. We suggest that paroxetine's antipruritic effect may be explained by rapid downregulation of the 5-HTs receptors, which may have an important role in the generation of pruritus and pain.