The activity, safety and tolerability of the azalide azithromycin were compared with those of co-amoxiclav in the treatment of acute periapical abscesses in adults in an open, randomized, multicentre comparative study. Patients of either sex, recruited from 106 dental practices in Belgium, were aged between 18 and 75 years and had acute periapical abscesses not requiring drainage, confirmed by radiology. Azithromycin was administered as a 500-mg tablet orally once daily for 3 days (n = 150) and co-amoxiclav as a 625-mg capsule three times daily, for 5-10 days (n = 153). Both before and after treatment, masticatory pain, percussion pain, headache, and oedema and redness of soft tissue were graded on a four-point scale. Overall clinical success (cure plus improvement) was seen in 131/144 (91%) evaluable patients receiving azithromycin and in 142/148 (96%) receiving co-amoxiclav (difference not significant). There was no significant difference between the two groups in the incidence or severity of adverse events or in the number of discontinuations because of adverse events.