The effect of hyperlipoproteinemia on systemic candidiasis was investigated by assessing the susceptibility of hyperlipoproteinemic, apolipoprotein E (ApoE)-deficient (ApoE -/-) mice to a systemic Candida albicans infection. The absence of ApoE in these mice resulted in an eightfold increase in plasma lipoprotein concentrations in the very low-density lipoprotein (VLDL) fraction, as compared with levels seen in ApoE +/+ mice. Mortality due to candidemia was significantly higher (86%) in ApoE -/- mice than in ApoE+/+ mice (52%), and in platings of homogenized kidney material on fungal culture medium, ApoE -/- mice yielded significantly higher levels of C. albicans outgrowth than did ApoE+/+ mice. C albicans grew twofold better in ApoE -/- plasma in 4 h than in ApoE+/+ plasma, and depletion of lipoproteins from plasma resulted in a significant seven- to tenfold increase in C. albicans growth. Recombinant ApoE did not directly inhibit C. albicans growth. Our data indicate that the increased susceptibility of ApoE -/- mice to C albicans is due both to increased growth of blastoconidia in ApoE -/- mice in response to the availability of lipids as nutrients, and to the neutralization of candidacidal factors by lipoproteins. This study suggests that lipoproteins play a significant role in host defense against candidiasis.