In the treatment of acute maxillary sinusitis, azithromycin offers an advantage over phenoxymethylpenicillin in that a complete course of treatment requires drug administration once daily for only three days. In this double-blind, parallel-group, multicenter study, 438 patients with radiographically verified maxillary sinusitis were randomly assigned to receive either 500 mg azithromycin once daily for three days (221 patients) or 1.3 g phenoxymethylpenicillin three times daily for ten days (217 patients). Nasal secretion, maxillary tenderness and pain, nasal obstruction, general malaise, and hyposmia, were assessed at the start of the study and on days 4, 11, and 25 of treatment. After 11 days 58% of the patients in the azithromycin group were cured versus 51% in the penicillin group; after 25 days the cure rate was 79% versus 76%, respectively. When both cure and improvement were considered, the corresponding figures after 11 days were 97% (azithromycin) and 95% (penicillin); after 25 days they were 92% and 88%, respectively. Adverse events, predominantly gastrointestinal, occurred in 73 (33%) of the azithromycin-treated patients and in 87 (40.1%) of those treated with penicillin. No difference in efficacy was found between the two drugs in the treatment of acute maxillary sinusitis, and the adverse effects were comparable. The short duration of treatment with azithromycin offers a significant advantage over treatment with phenoxymethylpenicillin.