BACKGROUND: Intrauterine Candida albicans infection causes severe fetal inflammatory responses and fetal injury in an ovine model. We hypothesized that intra-amniotic antifungal therapy with fluconazole would decrease the adverse fetal effects of intra-amniotic C albicans in sheep. METHODS: Sheep received an intra-amniotic injection of 10(7) colony-forming units C albicans. After 2 d, animals were then randomized to: (i) intra-amniotic and fetal intra peritoneal saline with delivery after 24 h (3 d C. albicans group); (ii) intra-amniotic and fetal intraperitoneal injections of fluconazole with delivery after either 24h (3 d C. albicans plus 1 d fluconazole group) or 72h (5 d C. albicans plus 3 d fluconazole group). Controls received intra-amniotic injections of saline followed by intra-amniotic and fetal intraperitoneal fluconazole injections. RESULTS: Intra-amniotic C. albicans caused severe fetal inflammatory responses characterized by decreases in lymphocytes and platelets, an increase in posterior mediastinal lymph node weight and proinflammatory mRNA responses in the fetal lung, liver, and spleen. Fluconazole treatment temporarily decreased the pulmonary and chorioamnion inflammatory responses. CONCLUSION: The severe fetal inflammatory responses caused by intra-amniotic C albicans infection were transiently decreased with fluconazole. A timely fetal delivery of antimicrobial agents may prevent fetal injury associated with intrauterine infection.