The first European isolate of meticillin-resistant Staphylococcus aureus (MRSA) was detected in 1960. Since then MRSA has become a leading cause of nosocomial infections worldwide. Using molecular typing techniques--primarily pulsed-field gel electrophoresis (PFGE)--we identified five major MRSA clones that accounted for almost 70% of the over 3000 MRSA isolates recovered in hospitals mainly in southern and eastern Europe, South America, and the USA. Most of our surveillance studies were done in these areas. Multilocus sequencing typing (MLST) of representative isolates of this collection showed that these five pandemic MRSA clones have evolved from only two distinct ancestral genetic backgrounds, one of which can be traced back to the very first European MRSA isolates and also to meticillin susceptible S aureus strains circulating in Danish hospitals during the mid to late 1950s--i.e., shortly before the introduction of meticillin into therapy. The second lineage with a completely different MLST profile included MRSA frequently recovered in the USA, Japan, and among paediatric isolates from several parts of the world. A few isolates with a third distinct MLST type corresponding to that of EMRSA-16 were also detected in the early Danish isolates. The four structural types of mec element, the heterologous DNA segment containing the meticillin resistance determinant mecA, were present in unique combinations with the MRSA clonal types. Our findings establish evolutionary associations in the most widely spread pandemic clones of MRSA. The epidemiological factors that contributed to the massive dissemination of a few MRSA clones are not well understood. We suggest, however, that the secrets of effectiveness of MRSA could be hidden in the unique genetic background of a surprisingly few lineages of S aureus particularly well able to cope with the contemporary clinical environment.