This study was performed in order to assess whether 500mg of azithromycin given orally once per week could produce tonsil tissue concentrations above minimum inhibitory concentrations for key target pathogens in patients with recurrent tonsillitis. For the measurement of tissue concentrations an automated solid phase extraction (SPE) method for cleaning the tissue extracts was developed. Concomitantly, the influence of this treatment on the microbiological flora of the tonsillar surface was monitored. The mean concentration of azithromycin in the tonsillar tissue was 1.8 microg/g (0.4 microg/g to 5.1 microg/g), i.e. therapeutic concentrations of azithromycin were found in most tonsils 1 week after medication. The validated SPE method developed provided a clean extract for high performance liquid chromatographic determination of azithromycin. The surface microbiology of the tonsils at surgery showed the usual pathogens in most patients. In conclusion, therapeutic levels of azithromycin were present in tonsil tissue during weekly medication with minimal influence on surface microbiology. A placebo-controlled, double-blind study of long-term treatment is in progress.