ImportanceBlood donors are at increased risk for iron deficiency. Current hemoglobin (Hb) monitoring policies are inadequate and new iron management strategies are warranted.ObjectiveTo determine the effects of ferritin-guided donation intervals for whole blood donors on Hb and ferritin levels, Hb deferral, iron deficiency (ferritin < 15 ng/mL) prevalence, donor return, and iron deficiency-related symptoms.DesignBetween November 2017 and November 2019 a ferritin-guided donation interval policy was gradually implemented nationwide and evaluated through a stepped-wedge cluster-randomized controlled trial.SettingAll blood collection centers in the Netherlands.Participants412,888 whole blood donors were included.InterventionsFerritin was measured in all new donors and at every 5thwhole blood donation. Subsequent donation intervals were extended to six months if ferritin is 15 ≤ 30 ng/mL and to twelve months if ferritin is <15 ng/mL (iron deficient).Main outcomes and MeasuresThe primary outcomes are ferritin and Hb levels, iron deficiency, Hb deferral, and donor return. Secondary outcomes are self-reported iron deficiency-related symptoms.ResultsWe measured 36,099 donors, median age 43 years and 52% female, making 37,621 donations during the study period. Ferritin-guided donation intervals increased log-transformed ferritin levels at all time points in the trial, up to 0.56 log-transformed ng/mL as compared to baseline (95% CI0.49 – 0.63, p <0.001). Hb increased as well, up to 0.39 g/dL (95% CI0.32 – 0.45, p <0.001). Decreased odds of 13% (95% CI8 – 22, p <0.001) for iron deficiency and 20% (95% CI6 – 47, p <0.001) for Hb deferral were reported compared to baseline. Odds of donor return decreased over the course of the trial, as low as 56% (95% CI48 – 66, p <0.001). We found no evidence for improved self-reported iron deficiency-related symptoms after implementation of the new policy.Conclusion and RelevanceFerritin-guided donation intervals significantly increased overall Hb and ferritin levels, thereby decreasing the prevalence of iron deficiency and Hb deferrals in whole blood donors. Ferritin-guided donation intervals seem beneficial for Hb levels and iron maintenance, but additional efforts are required to retain donors and to remedy self-reported iron deficiency-related symptoms.Trial RegistrationThis trial has been registered in the Dutch trial registry (NTR6738) on September 29th,, 2017 (https://trialsearch.who.int/Trial2.aspx?TrialID=NTR6738).