Cephalosporins are among the safest antibiotics. Nevertheless, hematologic abnormalities ranging from mono- to pancytopenia do occur, albeit infrequently, following their therapeutic use. Similar abnormalities to those reported in people have been seen in dogs given high doses of cephalosporins. As part of a study to define the latter thoroughly, we explored the effects of long-term, high-dose cephalosporin administration on canine marrow erythroid (CFU-E) and granulocyte-macrophage (CFU-GM) progenitor cells. Cefazedone (Refosporen, E. Merck, Darmstadt) was administered intravenously at doses of 540 to 840 mg/kg daily to 14 healthy beagle dogs for up to 4 months, or less if hematologic effects were evident earlier. Within 6 to 10 weeks, treated dogs developed pancytopenia (5/14), thrombocytopenia (11/14), moderate to severe neutropenia (8/14), and/or normocytic anemia (8/14). There was evidence of immune-mediated destruction of peripheral blood cells. All treated dogs exhibited a significant reduction in marrow colony-forming capacity, irrespective of whether peripheral cytopenia was present, with 12/14 showing decreased CFU-GM and 14/14 decreased CFU-E activity. Within a week following cessation of dosing, all affected dogs achieved hematologic remission as defined by restoration of the peripheral blood counts. However, despite this apparent recovery, both CFU-E and CFU-GM activities of the bone marrow remained depressed for at least another 8 months. We conclude that in dogs prolonged administration of high doses of cefazedone induced a persistent deficit of CFU-E and CFU-GM progenitor cells. The clinical relevance of this, if any, remains to be established.