This double-blind, randomized (1:1), 33 centre clinical trial compared the safety and efficacy of 250 mg clarithromycin (2 × l25mg capsules) 12-hourly and 250 mg ampicillin (one capsule) 6-hourly in the treatment of acute bacterial exacerbation of chronic bronchitis. Clinical and bacteriological evaluations were performed during treatment (study days 3–5, 8–10) and within 48 h following the end of therapy. Two hundred and twenty-five patients were included in the safety analysis. Both clarithromycin and ampicillin were effective with clinical success rates of 97% (28/29) and 91% (31/34), respectively. Pathogen eradication rates were 86% (36/42) for clarithromycin and 88% (37/42) for ampicillin. No significant difference in the number of patients reporting one or more adverse events was observed between treatment groups. Eleven clarithromycin and six ampicillin patients prematurely discontinued the study owing to adverse events. Clarithromycin 12-hourly was as safe and effective as ampicillin 6-hourly in the treatment of acute bacterial exacerbation of chronic bronchitis.