Therapeutic trials have confirmed the efficacy of a number of approaches to the treatment of single-system Langerhans cell histiocytosis (LCH). Not so well studied, but with some pharmacologic rationale and anecdotal reports of clinical success, are prostaglandin inhibitors. We present here a review of the possible mechanism of action of prostaglandin inhibitors in LCH and 2 cases of single-organ, single-site LCH treated with only prostaglandin inhibitors, both with sustained favorable clinical outcomes.