During the late 1990s, increases in referrals to the national reference laboratory of Streptococcus pyogenes isolates from injecting drug users (IDUs) with severe soft tissue infection indicated an emerging problem in the UK, later confirmed during the 2003-2004 European enhanced surveillance (Strep-EURO) programme. In light of these findings, further analyses were undertaken in an attempt to understand the reasons behind this increase in referrals. Single and multivariable analyses were undertaken to compare clinical, microbiological and demographic characteristics of IDUs diagnosed with severe S. pyogenes infection during the 2003-2004 enhanced surveillance study with those of other cases arising during this same period. Temporal and spatial analyses were undertaken for IDUs to identify clustering, as a means of understanding the transmission dynamics underpinning this increase. Infections in IDUs were spread across the UK, with some concentration in northern England and London. IDUs presented with a wide range of clinical manifestations, including pneumonia, which was found to be significantly more common in IDUs (OR 3.00) than in other cases. Marked differences in type distributions were found between IDUs and other cases, in particular the concentration of emm/M83 (22% of IDUs, 2% of non-IDUs). These findings indicate that an epidemic of severe S. pyogenes infections in IDUs occurred in the UK, peaking in 2003. The explanation for this rise remains unclear.