The spread of infectious virus in the tissues of mice after infection with two serologically very similar plaque mutants of Mengo virus has been determined at daily intervals. The distribution of L-Mengo (a large-plaque, virulent mutant) after intraperitoneal and intravenous administration was quite similar, indicating that after intraperitoneal injection this mutant spreads throughout the animal by way of the vascular system. Infectious virus was recovered from all tissues examined except the liver. In contrast, S-Mengo (small-plaque, avirulent) was recovered only from the spleen and lymph nodes after either intravenous or intraperitoneal injection. After intravenous injection, L-Mengo was cleared only very slowly from the bloodstream and at a rate similar to that of two strains of poliovirus. On the other hand, intravenously injected S-Mengo was completely cleared within 30 min. Starting at around 4 h post-inoculation, high titers of interferon were induced in the serum by L-Mengo, reaching a peak by 12 h and remaining elevated for at least another 12 h before declining. Since little or no interferon was found in the serum after intravenous injection of S-Mengo, heat- or ultraviolet-inactivated L-Mengo, or poliovirus types 1 and 3, it was concluded that the presence of circulating, replicating virus was required for induction. The significance of these results is discussed.