Menstruating women, with or without underlying bleeding disorders, are at increased risk for developing iron deficiency-related fatigue, even in the absence of anemia. Oral iron therapy has limitations which include poor absorption and non-adherence due to gastrointestinal side effects. We performed a prospective clinical trial of post-menarchal adolescent females with iron-deficiency with or without mild anemia and fatigue who received a standardized regimen of intravenous iron sucrose. The baseline mean (SD) hemoglobin was 11.96 g dl−1 (1.05) in 20 girls (ages 14–21 years); with a range of 10.3–14.1 g dl−1. In this cohort, intravenous iron was well tolerated and patients demonstrated a sustained increase in ferritin levels with means (SD) of 13.4 ng ml−1 (13.1) at baseline to 141.5 ng ml−1 (104.5) at 6 weeks and 85.2 ng ml−1 (128.4) at 6 months after the infusions. We used a standardized (Peds QLTM Multidimensional) fatigue scale to objectively measure fatigue and proxy scores by parents with mean screening scores (SD) of 35.2 (16.8) and 31.9 (19.6), respectively. We demonstrated a clinically significant improvement both in patient as well as parent fatigue scores (in 19 out of 20 subjects) at 6 weeks (Mean (SD) 58.3 (21.3) [P < 0.0001] and 57 (24.4) [P < 0.0001], respectively); as well as 3 and 6 months after the iron infusions. In nonanemic patients, iron administration did not significantly influence hemoglobin concentration. Therefore, the fatigue-reducing effects of iron therapy reflect the nonhematological functions of iron. Am. J. Hematol. 91:973–977, 2016. © 2016 Wiley Periodicals, Inc.