Blood donation is central to maintaining adequate blood supply for routine hospital demands and ensuring preparedness for emergency situations. As blood donation is a voluntary activity, it is important that blood collection services ensure that blood donor health is not negatively impacted in the strive to maintain blood supply. However, health-related consequences of frequent blood donation are not fully understood, and the relevance of iron supplementation remains unclear. Thus, the aim of this thesis was to investigate different aspects of blood donor health (including quality of life, iron levels and symptoms related to iron deficiency) and to summarise key characteristics of donors who may be able to safely give blood donations more frequently. The INTERVAL trial was a large pragmatic trial conducted to assess whether blood supply in the UK could be safely increased by reducing the interval between blood donations. A total of 45,263 UK blood donors (50% men and 50% women) were assigned to donate blood more frequently (men: 8 and 10 weeks; women: 12 and 14 weeks) than routine practice (men: 12 weeks, women 16 weeks). Interactions with randomised inter-donation interval were assessed to identify donor subgroups who may safely donate more frequently without affecting the trial’s key safety outcome - low haemoglobin deferrals. Mediation analyses were performed to assess whether iron supplementation during the trial mediated the effect of randomised inter-donation frequency on donor reported symptoms potentially associated with iron deficiency, including tiredness, breathlessness, palpitations, and fainting. Modelling was performed to assess the effect of more frequent blood donation on donors’ physical and mental wellbeing. Among 252,528 donor attendances during the 2-year period of the INTERVAL trial, 222,370 (88%) resulted in successful donation and 13,099 (5%) resulted in low haemoglobin deferrals. Donors randomised to shorter inter-donation intervals were able to give more donations, but also had higher frequency of low haemoglobin deferrals. Further interaction analyses conducted in this thesis suggested that increased frequency of donations with shorter inter-donation intervals was modified by age, donation history, iron multivitamin supplement use, physical and mental health scores and ferritin levels. The effect of randomised inter-donation interval on low haemoglobin deferrals was modified by baseline donation history, age, haemoglobin level and ferritin level. Donors randomised to shorter inter-donation intervals reported higher frequencies of symptoms such as tiredness, breathlessness, fainting or feeling faint, and palpitations. Use of iron supplementation, a commonly studied therapy for relieving symptoms such as fatigue, also increased during the trial. However, the effect of shorter inter-donation intervals on the frequency of symptoms was the same irrespective of adjustment for iron supplementation use before or during the trial. Donors in the INTERVAL trial had higher physical and mental health component scores (PCS, MCS) than the general population. While the PCS and MCS were associated with baseline characteristics such as age, weight, and previous diagnosis of anaemia, there was no significant effect of randomised inter-donation interval on any of PCS, MCS, or the eight sub-components that make up the two summary measures. The findings from this thesis may help inform future directions for blood donation practice and management in the UK and elsewhere. Characteristics of donors able to safely donate blood more frequently and those who may be at greater risk of low haemoglobin deferrals were identified. Impact on donors’ quality of life appears marginal. Some physical symptoms may be experienced by donors who donate more frequently, irrespective of iron supplementation use, suggesting need for further study to elucidate other mechanisms of mitigating post-donation symptoms.