Erythroderma is a rare, potentially life-threatening presentation of psoriasis that can be triggered by medication reactions. Bupropion is indicated for major depressive disorder (Wellbutrin®, GlaxoSmithKline, Research Triangle Park, NC), smoking cessation (Zyban®, GlaxoSmithKline, Research Triangle Park, NC), and weight loss (when in formulation with naltrexone ER; Contrave®, Orixegen Therapeutics, La Jolla, CA). Bupropion can exacerbate psoriasis, however, this is an under-recognized side effect of the medication, particularly in the United States. We report a case of bupropion-induced erythrodermic psoriasis in a 62-year-old female who was prescribed the medication for depression. Due to the common comorbidities of depression, obesity, and tobacco abuse in psoriatic patients, all for which treatment with bupropion is indicated, it is important for physicians to be aware of the potential for a life-threatening medication reaction in this patient population.