Polymicrobial polyarticular septic arthritis is a rare clinical entity, with only a few cases having been reported to date. We report a case due to Streptococcus pyogenes and Staphylococcus aureus in an IVDU, complicated by fatal streptococcal toxic-shock syndrome, and review the current literature. We conclude that whenever polymicrobial polyarticular septic arthritis is diagnosed, a high index of suspicion should be maintained for the detection of locally destructive infectious processes as well as systemic complications, and that a high mortality rate should be expected.