Infections caused by MRSA are increasingly involved as main health compromise in worldwide for hospitalized patients. Some MRSA clones have the ability to spread easier than others within the hospital environment and thereby are frequently implicated in outbreaks. The specific phenotypic and genetic factors contributing to the epidemic behavior of this bacterium have not been identified until present. We examined the invasion and intracellular survival of both epidemic and sporadic strains of Staphylococcus aureus within epithelial and macrophages cell lines as an essential step to study their involvement in the epidemic capacity. Both, epidemic and sporadic S. aureus strains showed similar intracellular growth during the first 60 min. of infection. Besides to survive within the eukaryotic cells, all epidemic strains but not the sporadic ones induced a significant necrotic-like cytotoxicity following 12 h. of infection. This effect correlates with the production of the á –toxin identified as a major excreted protein involved in a drastic reduction of cell viability. Thus, S. aureus can persist in clinical setting through biofilm formation for which the á -toxin is required. In conclusion, the higher cytotoxicity evidenced in this study reveal a biological feature of these bacteria explaining why some strains can persist in the environment and disseminate easier that others, conferring the epidemic behavior.