A main feature in the pathogenesis of bacterial endocarditis is the activation of the coagulation system via the extrinsic pathway, resulting in the formation of infected endocardial vegetations. Earlier studies gave indirect evidence that monocytes play an important role in the procoagulant response during the course of the disease. In this study, we assessed the role of monocytes more directly. We compared weights and tissue factor activities (TFA) of endocardial vegetations of normal rabbits infected with Streptococcus sanguis with those of rabbits which were treated with the cytostatic drug etoposide (Vepesid; Bristol-Myers Squibb B.V.) to induce a selective monocytopenia. Furthermore, the importance of the presence of bacteria was determined through the influence of antibiotic treatment on TFA, vegetational weight, and infection of the vegetations. The TFA of the vegetations was measured chromogenically by monitoring the factor VII-dependent activation of factor X with an amidolytic assay for factor Xa. We found that the degree of infection and the weight of vegetations of rabbits treated with the cytostatic drug etoposide did not differ from that of untreated rabbits. Their TFA, however, was significantly lower than the TFA of vegetations of rabbits not treated with etoposide. We also found that, as with the monocytopenic rabbits, the weight of the vegetations was not reduced in penicillin G-treated rabbits. The degree of infection and TFA, however, were significantly lower. We conclude that monocytes indeed are involved in the activation of the coagulation system during the course of bacterial endocarditis and that the degree of infection is positively correlated to the TFA of the vegetations.