Staphylococcal toxic shock syndrome (TSS) was originally described in menstruating women using high-absorbency tampons and linked to toxic shock syndrome toxin (TSST)-1 producing Staphylococcus aureus. Few studies have investigated the pathogenesis and treatment of TSS and contemporary clinical and moleculo-epidemiological descriptions are lacking. Clinical and molecular analysis of 180 TSS referalls to the UK reference laboratory between 2008-2012 was undertaken. Average annual TSS incidence was 0.08/100,000 population. Most cases were non-menstrual (nmTSS), related to skin and soft tissue infections and caused by tst+ clonal complex (CC) 30 MSSA. tst+ CC30 MRSA rarely caused TSS. Focussing on tst+ CC30 clinical strains, MSSA isolates produced more TSST-1 and superantigenic activity than MRSA isolates in vitro. A non-synonymous mutation in a tst regulator ccpA, ILE87, was detected in 33/39 CC30 MRSA strains that was associated with reduced TSST-1 production in vitro and SCCmecII. A murine abscess model of nmTSS was developed using tst+ CC30 S. aureus in TSST-1-sensitive transgenic HLA-DQ8 mice. Bacteria were detected in abscesses, lymphoid organs and blood. TSST-1 was detected in abscesses and draining lymph nodes, with detectable serum superantigen bioactivity. Mirroring in vitro findings, CC30 MSSA strains produced more TSST-1 in abscesses, and abscess and serum superantigenicity, than CC30 MRSA strains. TSST-1 expanded T cell Vβ subsets 3 and 13 in HLA-DQ8 mice. IL-6, IFNγ, KC and MCP-1 were consistently raised during infection. Clindamycin-containing antimicrobial regimens reduced abscess size and TSST-1 production. TSS in the UK is mainly non-menstrual and caused by tst+ CC30 MSSA strains producing more TSST-1 and superantigenic activity than MRSA counterparts. MRSA-TSS is extremely rare, perhaps due to altered tst regulation and diminished TSST-1 production. Clindamycin impaired TSST-1 production, supporting lincosamide use in treatment. This new nmTSS model should provide novel insight into S. aureus pathogenesis, especially TSST-1 production in situ within local lymphoid tissue.