Topical metronidazole has been available for clinical use in the United States for more than 15 years. Clinical trials evaluating metronidazole topical gel, 0.75%; metronidazole topical lotion, 0.75%; metronidazole topical cream, 0.75%; and metronidazole cream, 1% formulations are inclusive of more than 550 actively treated patients. Two recent studies gauging both the conventionally used 0.75% water-based gel and a 1% gel in a novel aqueous formulation are inclusive of more than 1800 patients. Although individuals with rosacea often exhibit an increased propensity to experiencing signs and symptoms of skin irritation, such as erythema, stinging, and burning, all currently available topical metronidazole vehicle formulations have demonstrated excellent tolerability profiles. This article reviews available data relevant to the cutaneous tolerability of topical metronidazole and reports on the results from a clinical study examining the frequency and severity of application site reactions to topical metronidazole used as monotherapy or in combination with other topical agents.