Iron deficiency is more prevalent in overweight children and adolescents but the mechanisms that underlie this condition remain unclear. The purpose of this cross-sectional study was to assess the relationship between iron status and excess adiposity, inflammation, menarche, diet, physical activity, and poverty status in female adolescents included in the National Health and Nutrition Examination Survey 2003-2004 dataset. Descriptive and simple comparative statistics (t test, chi(2)) were used to assess differences between normal-weight (5th < or = body mass index [BMI] percentile <85th) and heavier-weight girls (< or = 85th percentile for BMI) for demographic, biochemical, dietary, and physical activity variables. In addition, logistic regression analyses predicting iron deficiency and linear regression predicting serum iron levels were performed. Heavier-weight girls had an increased prevalence of iron deficiency compared to those with normal weight. Dietary iron, age of and time since first menarche, poverty status, and physical activity were similar between the two groups and were not independent predictors of iron deficiency or log serum iron levels. Logistic modeling predicting iron deficiency revealed having a BMI > or = 85th percentile and for each 1 mg/dL increase in C-reactive protein the odds ratio for iron deficiency more than doubled. The best-fit linear model to predict serum iron levels included both serum transferrin receptor and C-reactive protein following log-transformation for normalization of these variables. Findings indicate that heavier-weight female adolescents are at greater risk for iron deficiency and that inflammation stemming from excess adipose tissue contributes to this phenomenon. Food and nutrition professionals should consider elevated BMI as an additional risk factor for iron deficiency in female adolescents.