We have investigated the ability of two strains of the parvovirus minute virus of mice to impair mouse hematopoiesis in vitro. We found that the BFU-E and CFU-GM committed progenitors, CFU-Mix pluripotent progenitor, as well as the CFU-S12d, one of the most primitive hematopoietic precursors of the stem cell compartment detectable by colony technique, were similarly inhibited in their proliferative capacity by the immunosuppressive strain MVMi, but not by the prototype virus MVMp. The inhibitory effect correlated with the input of purified MVMi and was reversed by neutralizing MVM antiserum, showing that cytotoxic mechanisms underlying infectious MVMi replication and not operating in MVMp-infected cells were responsible for the reproductive death of hematopoietic precursors. In agreement with this, myeloid nonadherent cells of long-term bone marrow cultures were selectively permissive for MVMi but not for MVMp replication, as judged by viral DNA synthesis, the expression of the nonstructural cytotoxic NS-1 protein, and virus propagation in these cells. Altogether, the suppressive effects mediated by the MVMi cytotoxic infection define a wide lympho-myelotropism not previously reported for this virus. The MVM-mouse model highlights the role that unsuspected virus-hematopoietic compartment interactions may play in bone marrow failures of immunocompromised animal or human hosts.