The clearance of Sindbis virus from the blood stream and its localization in the reticuloendothelial system (RES) was studied in mice susceptible (2 weeks old) and resistant (6 weeks old) to fatal Sindbis virus encephalitis. No significant differences in the relative capacity of 2-week-old and 6-week-old mice to remove 125I-labeled virus from the blood stream and to localize virus within the liver were observed. However, the decline of infectious virus was more rapid in the blood of adult mice. These studies suggest that, in addition to physical removal of virus by the RES, inactivation of virus in the blood stream plays an important role in limiting viremia during infections with Sindbis virus.