We conducted a prospective multicenter study of methicillin-resistant S. aureus (MRSA), including the first five consecutive clinical isolates, collected between September 2006 and February 2007 in 23 hospitals located throughout France. The 111 isolates were tested for their antibiotic susceptibility patterns and were extensively characterized by screening for drug resistance and agr alleles, multilocus sequence typing (ST), staphylococcal cassette chromosome mec (SCCmec) typing, spa typing, and PCR profiling of 21 toxin genes. Clones were designated by their ST followed by their SCCmec type (I to VI). Lyon clone ST8-IV or -IVvariant (n=77, 69.4%) was widely distributed. Four minor clones were also detected, namely the “classical” pediatric clone ST5-IV (n=9, 8.1%), the “new” pediatric clone ST5-VI (n=8, 7.2%), the clone Geraldine ST5-Itruncated (n=7, 6.3%) and the European clone ST80-IV (n=4, 3.6%). The six other isolates were related to five rare clones. Relative to other European countries, the situation in France is marked by a predominance of a specific major clone and the worrying emergence of minor clones with enhanced virulence and new antibiotic susceptibility profiles.