BALB/cJ (H-2d) mice were injected intraperitoneally (ip) with cyclophosphamide 2 days after ip inoculation with Coxiella burnetii Nine Mile, phase I. Ten days after infection, disseminated microabscesses, granulomas, and microthrombi were observed in most organs, including spleen and liver, and in bone marrow. In addition, endocarditis of the atrioventricular and semilunar valves, characterized by macrophages and neutrophils, was present. At the same time, C. burnetii antigen was found in most organs and in cardiac valves, aorta, and pulmonary artery, mainly within macrophages, neutrophils, and endothelial cells. C. burnetii-specific IgG antibodies were detected 150 days after infection but not in the early phase of infection. Cardiac valves were devoid of C. burnetii antigen and without residual lesions at 150 days. These findings offer the possibility for further studies on the pathogenesis of C. burnetii-associated valvular endocarditis and show that acute strains of C. burnetii can cause endocarditis as a part of a disseminated infection in the immunocompromised host.