Von Magnus particles of influenza virus and defective interfering T particles of vesicular stomatitis virus were unable to provide significant protection of mice from disease or death when inoculated intranasally or intracerebrally along with moderate or high doses of homologous infectious challenge virus. However, yields of infectious virus from the affected organs were reduced as compared to controls inoculated with infectious virus alone. Serial intracerebral passage of vesicular stomatitis virus in mouse brain at high doses failed to produce T particles detectable by in vitro autointerference assays on BHK(21) cells, whether or not T particles were introduced along with B virions at the first passage. When very low challenge doses of infectious B virions were inoculated intracerebrally along with high doses of homologous defective particles, there was significant prolongation of life, although most mice died eventually of slowly progressing disease. Also, the virus yields in the brains of these mice were significantly reduced, and virus was no longer detectable in the brains of "protected" mice surviving for 10 days or more. Our results suggest that although homologous autointerference does occur in vivo, it is a more complex phenomenon than in vitro cell culture experiments might indicate.