Diabetes mellitus 2 (DM2), a serious, chronic condition, affects 40 million U.S. persons and one billion worldwide. The condition is characterized by unusually elevated blood glucose, insulin-resistance, and a pro-inflammatory state. We discuss data fulfilling the four Koch’s postulates, demonstrating that Staphylococcus aureus may cause DM2. First, patients are chronically infected with high levels of skin S. aureus, producing pro-inflammatory superantigens, compared to 17% of healthy persons colonized on skin with small numbers. Second, S. aureus is easily cultured from patients and shown to produce the superantigens toxic shock syndrome toxin-1, enterotoxin B, or enterotoxin C. Superantigens traverse skin barriers after interaction with CD40 and gp130 receptors. Third, S. aureus superantigens cause elevated blood glucose and insulin-resistance in experimental rabbits. S. aureus is easily re-isolated, fulfilling the fourth of Koch’s postulates. The data suggest that S. aureus superantigens cause DM2. Insights into this etiology may lead to cure or sustained remission.