The defect in host defense that makes the diabetic ketoacidotic (DKA) patient susceptible to mucormycosis has not been identified. Sera from 10 DKA patients and three normal volunteers were tested for their capacity to support the in vitro growth of a common etiologie agent of mucormycosis, Rhizopus oryzae. After equilibration with room air none of the normal or DKA sera, each of which was now extremely alkaline, supported growth of R. oryzae. When the sera were placed in a CO₂ atmosphere that permitted simulation of the in vivo clinical pH (normal 7.40 and DKA 7.3–6.6), four of seven DKA sera supported profuse fungal growth. No growth occurred in normal serum. The three DKA sera that did not support fungal growth at pH ≤7.3 contained less iron (× = 13 μg/dl) than the four sera that supported profuse fungal growth (× = 69 μg/dl). Increasing the iron content of iron-poor DKA serum that did not support R. oryzae growth allowed profuse growth at acidotic conditions but not at pH ≥7.4. Simulated acidotic conditions (pH 7.3–6.6) also decreased the iron-binding capacity of normal serum stepwise from 266 μg/dl to 0. Our data indicate that acidosis temporarily disrupts the capacity of transferrin to bind iron and suggest that this alteration abolishes an important host defense mechanism that permits growth of R. oryzae.