The susceptibility of 40 erythromycin-resistant isolates of Streptococcus pyogenes and 40 multiply-resistant isolates of Streptococcus pneumoniae to six macrolide antibiotics, representing 14-, 15- and 16-membered lactone ring structures, was tested. The genetic basis for macrolide resistance in the strains was also determined. Both erm and mef determinants were encountered in the 36 S. pneumoniae isolates tested, but only mef in the five S. pyogenes isolates tested. All isolates showed cross-resistance among the 14-membered macrolides erythromycin, clarithromycin and roxithromycin and the 15-membered macrolide, azithromycin. However, the erythromycin-resistant S. pyogenes isolates retained full susceptibility to spiramycin and josamycin (16-membered agents). These latter two antibiotics were also more active than the other macrolides against erythromycin-resistant S. pneumoniae isolates, especially josamycin which was 8-64 times more active than erythromycin; spiramycin was only two to eight times more active than erythromycin.