Tumor necrosis factor (TNF) is a novel immunotherapy for type I diabetes because it selectively kills insulin autoreactive T-cells, which enables recovery of insulin production by pancreatic islet cells. The TNF inducer Bacillus Calmette-Guerin (BCG) also has therapeutic value by activating innate immunity that beneficially modifies the course of type 1 diabetes (T1D) in the same manner as TNF. Epstein Barr Virus (EBV) infection is also an inducer of TNF. This observational study was undertaken to determine whether EBV has the same beneficial effects as BCG in a recent clinical trial. We describe three cases of long-term diabetic subjects with active mononucleosis that were followed for 15 weeks to determine the impact of EBV infection on established T1D. In comparison to non-EBVinfected long-term diabetics, EBV transiently diminished the autoimmune response in two of three cases. EBV infection triggered rapid increase of circulating insulin-B autoreactive T-cells whose striking loss of CD8 marker indicated that the cells were injured or apoptotic. EBV infection also caused a transient surge in the secretion of C-peptide, a marker for pancreatic insulin secretion. EBV acts like BCG in eliciting innate immunity and beneficially modifying the course of TID.