BACKGROUND Metronidazole 0.75% gel and azelaic acid 15% gel are commonly used to treat rosacea. Irritation is a common side effect. OBJECTIVE To assess the cumulative irritation potential of metronidazole 0.75% gel and azelaic acid 15% gel. METHODS Metronidazole 0.75% gel, azelaic acid 15% gel, and a white petrolatum negative control were applied under occlusive conditions to the upper back of a total of 33 healthy subjects. There were twelve 24-hour applications (4 times a week) and three 72-hour applications on weekends during a 3-week period. Skin reactions (erythema score +/- other local reaction) were assessed within 15 to 30 minutes of removal of the products. RESULTS The mean cumulative irritancy index of metronidazole 0.75% gel was significantly lower than that of azelaic acid 15% gel and not significantly higher than the negative control product. There was increasing cumulative irritancy with azelaic acid; no cumulative irritancy was seen for either metronidazole or white petrolatum. CONCLUSION Metronidazole 0.75% gel is less irritating in sustained use than azelaic acid 15% gel.