An evolutionary perspective suggests that iron deficiency may have opposing effects on infectious disease risk, decreasing susceptibility by restricting iron availability to pathogens, and increasing susceptibility by compromising cellular immunocompetence. In some environments, the trade-off between these effects may result in optimal iron intake that is inadequate to fully meet body iron needs. Thus, it has been suggested that moderate iron deficiency may protect against acute infection, and may represent a nutritional adaptation to endemic infectious disease stress. To test this assertion, we examined the association between infection, reflected by C-reactive protein, a biomarker of inflammation, and iron status, reflected by transferrin receptor (TfR) and zinc protoporphyrin to heme ratio (ZPP:H), among school-age Kenyan children, and evaluated the hypothesis that moderate iron deficiency is associated with lower odds of infectious disease. TfR > 5.0 mg/l, with sensitivity and specificity for iron deficiency (ZPP:H > 80 micromol/mol) of 0.807 and 0.815, was selected as the TfR definition of iron deficiency. Controlling for age and triceps skinfold thickness (TSF), the odds ratio (OR) for acute viral or bacterial infection associated with iron deficiency (compared to normal/replete) was 0.50 (P = 0.11). Controlling for age and TSF, the OR for infection associated with an unequivocally iron replete state (compared to all others) was 2.9 (P = 0.01). We conclude that iron deficiency may protect against acute infection in children.