Abstract Background Blood donors are at risk for reduced iron stores, because of which donor iron monitoring received increased attention in the last decade. Despite the importance for donor health, international consensus on an appropriate policy for iron monitoring is lacking. Therefore, we conduct a trial to evaluate to what extent ferritin-guided donation intervals are effective in increasing haemoglobin and ferritin levels, decreasing low-haemoglobin deferral, increasing donor return and improving the health of whole blood donors in the Netherlands. Methods Sanquin Blood Bank is implementing ferritin-guided donation intervals to prevent donors from increasing iron loss at repeated donations. Using a stepped wedge cluster randomised trial approach, the design involves a random crossover of 29 clusters of blood collection centres from the existing policy without ferritin measurements to a ferritin-guided donation interval policy. This new policy includes ferritin measurements for all new donors and at every 5th whole blood donation, extending donation intervals to 6 months if ferritin is 15–≤ 30 ng/mL and to 12 months if ferritin is < 15 ng/mL. We measure ferritin levels of whole blood donors from stored plasma samples and collect haemoglobin levels and information on low-haemoglobin deferral and donor return from the donor database before, during and after the implementation period. We measure donor health during and after the implementation period using questionnaires, assessing physical and mental wellbeing and iron deficiency- and donation-related symptoms. We use multilevel analyses to investigate differences in ferritin and haemoglobin levels, low-haemoglobin deferral rates, donor return and donor health from whole blood donors, between blood collection centres that have versus those that have not yet implemented the ferritin-guided donation interval policy. Discussion This stepped wedge cluster randomised trial will provide insight into the effectiveness of ferritin-guided donation intervals in lowering iron deficiency, decreasing donor deferrals due to low haemoglobin and improving donor health. We will evaluate a policy that is implemented nationwide in a real-life setting. Our study is therefore not limited to a small experimental setting and the results will guide policymakers seeking an appropriate policy for iron monitoring. Trial registration The Dutch trial registry NTR6738. Registered on 29 September 2017. Retrospectively registered.