Candida albicans is a pleomorphic fungus with budding yeast and filamentous forms, and is a frequent cause of complicating infections in patients who are postsurgical, in shock, and have trauma. Many cases of systemic candidiasis are thought to orginate from the intestine, but it is unclear if the filament or the yeast is the more invasive form. Because C. albicans is relatively noninvasive and because mesenteric ischemia is thought to facilitate extraintestinal microbial dissemination, wild-type C. albicans CAF2 and mutant HLC54 (defective in filament formation) were orally inoculated into antibiotic-treated mice that were housed exclusively in room air, or were intermittently exposed to 10% oxygen for 1-h intervals. Both strains of C. albicans colonized the cecum in similar numbers (approximately 10(6.7)/g). C. albicans translocation to the draining mesenteric lymph nodes was not detected in mice inoculated with CAF2 (normoxic or hypoxic) or in normoxic mice inoculated with HLC54, but was detected in 33% (P < 0.01) of hypoxic mice inoculated with HLC54. Using Caco-2 and HT-29 enterocytes cultivated on plastic dishes and pretreated for 48 h in 10% oxygen, adherence of C. albicans HLC54 was decreased compared with wild-type CAF2, and hypoxia had no noticeable effect on adherence of either CAF2 or HLC54. Using enterocytes cultivated on permeable 8-microm filters, transepithelial migration of C. albicans CAF2 and HLC54 appeared similar. Thus, C. albicans HLC54 (defective in filament formation) was more invasive in hypoxic mice compared with wild-type CAF2, and host factors (e.g., mesenteric ischemia) rather than an innate ability to interact with enterocytes might play a more important role in extraintestinal dissemination of C. albicans yeast forms.