Panton-Valentine leukocidin (PVL)-positive methicillin-resistant Staphylococcus aureus (MRSA) that are multi-locus sequence type clonal complex 22 (CC22) comprise a significant public health problem in the UK. In the present study we sought to determine the genetic diversity, and the respective patient demographics, among 47 PVL-MRSA with a CC22 pulsotype that occurred sporadically or in clusters in community and healthcare settings in eight of nine geographic regions in England and Wales between January 2005 and September 2007. Patient demographics and disease presentations were typical for PVL-S. aureus infections (mostly skin and soft tissue infections in individuals <40 years old); one patient with community-acquired pneumonia died. Although the isolates were closely genotypically related by spa typing and pulsed field gel electrophoresis, at least two variant groups were suggested. PCR detections demonstrated that the majority of the CC22 PVL-MRSA identified (n = 42; 89%) harboured SCCmecIVc, three had SCCmecIVd, one had SCCmecIV but was non-subtypeable, and one isolate harboured SCCmecV. At least three different PVL-encoding phages were detected: ФPVL, Ф108PVL and an unidentified icosahedral phage. Agar dilution MIC determinations showed that the CC22 PVL-MRSA identified were typically resistant to gentamicin and trimethoprim (43 of 47 isolates) and ciprofloxacin resistance was also noted in six isolates. In conclusion, the CC22 PVL-MRSA tested were geographically disseminated but highly genetically related. The observed variances in acquired elements (most notably SCCmec and PVL-encoding phages) suggested that CC22 PVL-MRSA in England and Wales have evolved on multiple occasions.