Osteopontin (OPN) is a phosphorylated glycoprotein that has been implicated in a number of infectious diseases. However, the role of OPN in Streptococcus pyogenes infection is unknown. To investigate whether OPN is involved in S. pyogenes infection, we first examined the plasma OPN levels after local injection of S. pyogenes. OPN expression was significantly increased at 2 h post-infection and increased thereafter. A correlation was found between plasma OPN levels and the development of S. pyogenes infection. The plasma OPN level in severe S. pyogenes infection was higher than during a normal infection. Levels of OPN were found to correlate with the severity of S. pyogenes infection. We also found that OPN production was suppressed by interleukin-6 and enhanced by tumour necrosis factor-alpha in immunocompetent cells. Collectively, these findings demonstrate that the OPN level may provide clues to the severity of S. pyogenes infection in the early phase of the infection.