About 30% of Friend virus (F-MuLV-P)-infected C57BL/6 mice became leukemic more than ten weeks after virus infection. This late leukemia development could not be essentially influenced by drug treatment, such as injection of hydroxyurea (2 X 500 mg/kg), actinomycin D (3 X 120 micrograms/kg), phenylhydrazine (3 X 60 mg/kg), or 30 micrograms endotoxin or by bone marrow transplantation following lethal irradiation. Endotoxin (30 micrograms) given prior to virus caused the loss of resistance to F-MuLV-P, but it had only a slight effect if applied one or three months after virus infection. Leukemia development has never been observed in C57BL/6 mice after splenectomy. In DBA/2 mice, highly susceptible to F-MuLV-P, leukemia development was markedly impaired if the mice were splenectomized. These results clearly indicate that the spleen plays a crucial role in the mechanism of susceptibility or resistance to the Friend virus.