Objectives/Hypothesis: Chronic rhinosinusitis (CRS) recalcitrant to surgery is a frustrating clinical entity. Recently, mupirocin sinonasal rinses have been suggested as an efficacious treatment alternative in these patients where Staphylococuccus aureus infection is demonstrated. To our knowledge, how best to treat this S aureus reservoir has not been previously evaluated in a double-blinded, randomized, placebo-controlled trial. Study Design: Prospective, double-blinded, placebo-controlled study. Methods: Twenty-five S aureus-positive CRS patients with persistent sinonasal infection despite endoscopic sinus surgery received either a 1-month, twice-daily treatment course of mupirocin sinonasal rinses (MUP) or saline rinses (CON). The primary outcome was S aureus-culture negativity at the conclusion of treatment; secondary rhinological outcomes included subjective and objective measures of rhinosinusitis. Results: Twenty-two patients satisfactorily completed the treatment period. Of CON patients, 0/13 (0.0%) returned an S aureus-negative sinonasal culture at 1month, compared to 8/9 (88.9%) of MUP patients (P <.01). Improvements in rhinological outcomes observed in MUP patients following treatment were not subsequently evident when these patients were followed up at a delayed assessment 2 to 6 months after completing treatment. Conclusions: Mupirocin sinonasal rinses are an effective short-term anti-S aureus treatment in surgically recalcitrant CRS as assessed by microbiological and selected rhinological outcomes, although the latter improvements may not be durable with time.