Systemic infection with Histoplasma capsulatum induced a granulomatous inflammatory response in the lymphoreticular organs of C57BL/6 mice that was associated with elevated levels of angiotensin-converting enzyme (ACE) in the spleens. To determine the influence of ACE on the granulomatous response, either captopril or MK 421, two inhibitors of ACE, were administered intraperitoneally to mice 6 h after intravenous injection of H. capsulatum and then daily for 1 week. Each ACE inhibitor sharply reduced ACE activity in the spleens of infected mice. Both drugs worsened the clinical severity of infection and significantly increased the growth of H. capsulatum in livers and spleens of mice infected for 1 week. The histopathological changes in mice given captopril were more severe, with massive infiltrates of macrophages in proximity to large aggregates of yeasts. Conversely, the administration of captopril for 2 weeks during the resolving phases of infection did not slow the healing of the granulomatous lesions, nor did it provoke a relapse of infection. Captopril did not promote the growth of H. capsulatum in artificial medium. This drug was not cytotoxic to peripheral blood leukocytes or to splenic leukocytes from normal and infected mice. Administration of captopril to normal mice for 1 week did not depress the response of splenocytes of concanavalin A or to phytohemagglutinin, nor did it diminish delayed-type hypersensitivity responses in vivo. Finally, captopril did not augment the growth of H. capsulatum within macrophages. Our results suggest that ACE may participate in the regulation of the granulomatous inflammatory response to H. capsulatum and that ACE inhibition impairs the protective effects of granulomatous inflammation during acute H. capsulatum infection.