BackgroundDespite having known detrimental effects on physical and cognitive performance, iron deficiency (ID) remains the most common micronutrient deficiency in the world. Many interventions aiming to improve iron status involve high‐risk, physically active populations such as manual laborers or athletes. Intense aerobic exercise training has been shown to negatively affect iron status; however, the impact of regular aerobic exercise on the efficacy of iron supplementation in improving iron status remains unclear.ObjectiveTo determine whether regular aerobic training modifies the efficacy of iron supplementation in improving iron status.Methods339 women were screened for a randomized control trial, of which 72 were found to be iron depleted with no or mild anemia at baseline (serum ferritin (sFer) <25 μg/L and hemoglobin (Hb) >90 g/L) and included in this study. A double‐blind study was conducted with a 2×2 design including iron supplements (42mg elemental iron/day) or placebo and daily aerobic training (5 sessions/week of 25 minutes at 75–85% maximum heart rate) or no training. Repeated measures ANOVA was used to evaluate the relationship between supplement type, training, and final changes in iron status as measured by sFer, Hb, transferrin receptor (sTfR), and body iron.ResultsThere were no differences in age, weight, height, percent body fat, iron measures, inflammation, or physical fitness between the four treatment groups at baseline. Additionally, there were no differences in the number of iron or placebo capsules consumed by each of the four groups or the number of training sessions attended by the two training groups. At endline, the iron group showed a significant increase in sFer (23.6 μg/L, p<0.01), whereas the placebo group showed no change over time (6.0 μg/L, NS). Similarly, the trained group showed a significant improvement in fitness, assessed as VO2max (3.8 mL/min/kg, p<0.01), whereas there was no change in the untrained groups (−0.89 mL/min/kg, NS). There was a significant time by supplement by training group interaction in models predicting sFer (p<0.01). Specifically, the iron trained group had a significantly lower change in sFer than the iron untrained group (−15.8 μg/L, p=0.03). The same result was seen for body iron. The interactions observed between supplement and training group for predicting sFer and body iron remained significant when Hb was included as a covariate in the models.ConclusionsThe data from this study suggest that regular aerobic training reduces the efficacy of iron supplementation in improving iron status. Improvements in both iron stores (sFer) and body iron were negatively affected by training and this effect was independent of change in Hb. No net Hb change was observed in the placebo trained group, suggesting that the observed training effect on iron response is not due to increased Hb demand. Further analyses could help clarify what is driving the modifying effect of exercise on supplement efficacy (iron absorption, reduced energetic efficiency, etc.). These findings indicate that interventions targeted at improving iron status may be less effective in physically active populations, which should be further studied to identify the optimal strategies for iron delivery in these groups.Support or Funding InformationFunding: Fulbright US Student Fellowship, Cornell Lehman Fund, Foreign Language Area Studies, Cornell Human Ecology Alumni Association, Cornell College of Agriculture and Life Sciences Alumni Association, N.S. Meinig Professorship