Evidence is presented that defective interfering (DI) Semliki Forest virus (SFV) can modulate the systemic infection in mice initiated by intraperitoneal inoculation of 10 LD50 SFV. Either the mean time of death was delayed or mice failed completely to develop any sign of disease. This prophylactic activity of DI virus was not due to the stimulation of an adaptive immune response since an equivalent amount of noninfectious virus antigen did not change the course of disease.