Background: Murine acquired immunodeficiency syndrome (MAIDS) is characterized by generalized lymphoproliferation and progressive immunodeficiency. It is induced by a mixture of two replication-competent murine leukemia viruses (MuLV) and a disease-causing, replication-incompetent defective MuLV. Infection leads to specific phenotypic and functional alterations of lymphocytes in lymphoid organs. Methods: We analyzed phenotypic, virological and functional parameters in the blood of mice infected with MAIDS virus. Results: Disease progression correlated with increasing viremia, a loss of mitogen responsiveness of T lymphocytes, and the appearance of CD4+ Thy1– T lymphocytes. At >9 weeks after infection, the distribution of leukocyte cell populations became very heterogeneous, and late-stage leukemic events were observed in 5 of 23 mice. Conclusions: Virus titers, mitogen responsiveness and the presence of CD4+ Thy1– T lymphocytes can efficiently be monitored in the blood and serve as diagnostic parameters to monitor disease progression. Acute leukemic events occurring at the terminal stage could be responsible for the death of at least some of the mice with MAIDS.