Purpose: To address iron deficiency in adolescent female cross country runners, a twelve week prospective clinical trial was conducted to analyze the efficacy of daily versus weekly iron therapy. Design: 47 female cross country runners [ages 14-18 years] were screened for iron deficiency [ferritin <20mg/dl] before the season. The participants were randomized to the daily treatment group[648mg FeSO4 qd (910mg elemental iron/wk)] or the weekly group [648mg FeSO4q week (130 mg elemental iron/wk)]. Intention to treat analysis, with paired t test and Mann Whitney U for nonparametric test for treatment group differences, was used. Results: The two groups had similar baseline parameters including demographics, aerobic fitness, hematologic indices [hemoglobin, hematocrit, ferritin, MCV, transferrin saturation] and iron absorption [analysis uses thermal ionization mass spectrometry of multiple-trace stable isotope using 58Fe administered prior to therapy and 57Fe after 6 weeks of therapy]. Of 17 runners who qualified for the study, 10 runners [4 daily, 6 weekly] completed the study protocol [2 refused to participate after the screening process, 5 (4 daily, 1 weekly, p=.15) were excluded because of noncompliance (less than 50% of prescribed medication)]. Side effects from the medication were related to noncompliance (p=.03). Those who were compliant in the daily group had a greater increase in their ferritin concentration [daily 19.0±8.2, weekly 3.5±5.0, p=.01] and final ferritin level [daily 34.2±6.5, weekly 15.0±9.9, p=.01]. Intention to treat analysis demonstrated no difference between treatment groups in hematologic indices and aerobic fitness. Over the study period, iron absorption in the daily group decreased by 71% [initially 20.5±4.9 to 6.0±5.9], while the weekly group decreased by 49% [initially 29.6±18.5 to 15.1±6.4], not significantly different (p=.20). The total amount of elemental iron incorporated per week for the daily group was 2.7 times the weekly group[daily 49.5±48.8mg, weekly 17.7±7.5mg, p=.67] and only 2.5 times the weekly dose when reported compliance was used [daily 38.7±mg, weekly 15.3±mg, p=.83]. Conclusions: Noncompliance and decreased iron absorption limit the effectiveness of daily iron therapy. One hypothesis is that higher weekly or twice weekly dosing may optimize absorption compliance.