The development and persistence of Sendai virus-specific CD4+ T cell memory has been analyzed following respiratory infection of C57BL/6J mice by determining the prevalence of IL-2-producing Th cell precursors (Thp). Frequencies as high as 1:40 virus-specific CD4+ T cells were found in the regional lymph nodes and spleen during the acute phase of the host response and persisted at levels > or =1:500 for 2 to 3 mo. Thereafter, these CD4+ T cells tended to distribute more to the spleen than to the lymph nodes, a pattern that persisted for the life of the animals. From 3 to 12 mo after infection, virus-specific Thp were always detectable, although the numbers were diminished relative to those measured during the acute phase. Thereafter, however, in both contemporary and cumulative assays, there was a progressive increase in both the frequency and number of Thp. These increases were especially apparent for mice more than 2 years of age. This may reflect enrichment of the CD4+CD44high memory set due to the gradual diminution of the naive CD4+CD62LhighCD44low component. Analysis of DNA staining profiles for the CD4+ T cells showed high levels of cycling for the acute phase of the response, whereas the rate of T cell turnover measured for the CD4+CD44high population by bromodeoxyuridine incorporation indicated a pattern of stable, continuing proliferation throughout life. Virus-specific CD4+ T cell memory resulting from a single exposure to a readily eliminated RNA virus is thus maintained indefinitely in laboratory mice.