We aimed to enhance our case ascertainment of meticillin-resistant Staphylococcus aureus encoding Panton-Valentine leucocidin (PVL-MRSA), determine the patient demographic, risk factor and disease associations, and define the clonal diversity amongst isolates referred to the UK Health Protection Agency's Staphylococcus Reference Unit. PVL-MRSA collected during 2005-6 from community-based and hospitalised patients located across England and Wales were identified by polymerase chain reaction (PCR). Representative geographically and temporally unrelated isolates were characterised via toxin gene profiling, SCCmec, spa and agr typing, multilocus sequence typing (MLST) and minimum inhibitory concentration (MIC) determinations. PVL-MRSA were identified from 275 patients. Affected individuals were <1 to 95 years of age (mean 30, median 27 years). Forty-five isolates were from 18 household or community-based clusters and 23 isolates were from outbreaks in healthcare settings. Overall, 58% (n = 161) had skin and soft tissue infections and 9% (n = 25) presented with or developed more serious disease, including eight patients (3%) with necrotising pneumonia, five of whom subsequently died. PVL-MRSA were genetically diverse and harboured SCCmecIV or V(T)/VII. Representatives of MLST clonal complexes (CCs) 8, 30 and 80 were identified the most often. The 275 PVL-MRSA included internationally disseminated community-associated MRSA (CA-MRSA) strains, as well as other minor lineages, and were associated with typical risk factors and disease presentations.