Multidrug resistant strains of Staphylococcus aureus are a major cause of skin and soft tissue infections requiring the development of novel and alternative therapeutic options. Photodynamic oxidation is the cornerstone of antimicrobial photodynamic therapy (aPDT) involving the combined use of light and a photosensitizer, which, in the presence of oxygen, originates cytotoxic species capable of oxidizing biological molecules and leads to inactivation of target cells. We have previously shown that susceptibility to aPDT differs significantly across S. aureus isolates and could be associated with several genetic elements. However, the effect of the photodynamic process regarding the S. aureus genetic background has never been reported. We have compared the genetic backgrounds of the strains (SCCmec types, spa types and main clonal complexes) with respect to their susceptibility to protoporphyrin IX-mediated photodynamic inactivation. SCCmec typing revealed no differences in response to photoinactivation. However, detection of spa types and clonal complexes clustered the studied population of MRSA strains according to their response to photodynamic oxidation. Clonal complex 1 (CC1) accounted for elevated resistance and CC30 (ST36) for susceptibility to photoinactivation. Moreover, spa typing identified isolates resistant (t032) and susceptible to photodynamic oxidation (t051, t015). The very tight association between clonal lineages and response to photodynamic inactivation indicates the important role of genetic background for aPDT efficacy. These results make a case for the development of a diagnostic tool with the predictive value of aPDT efficacy according to an identified genetic background of S. aureus isolates.