Resistance mechanisms and clonal relationships were determined for six Streptococcus pyogenes isolates with low- or high-level ciprofloxacin resistance. Four isolates displayed reduced susceptibility to ciprofloxacin and levofloxacin and had alterations in ParC: Ser80-->Pro (isolate emm3.1); Ser79-->Ala (two isolates emm6.0); and a double substitution Ser79-->Phe and Ala121-->Val (isolate emm12.27). Two isolates (emm12.26) displayed high-level resistance to ciprofloxacin and levofloxacin, as well as to other quinolones. These isolates had the same double substitution in ParC as isolate emm12.27, and an additional substitution (Ser81-->Tyr) in GyrA. Resistance patterns, emm typing and sequencing of the quinolone resistance-determining regions defined two clusters containing three and two isolates, respectively.