Blood donors have made important contributions to research, most notably in cross-sectional seroprevalence studies. The proposed New Zealand Blood Donors Health Study is a prospective cohort study of 30,000 New Zealand donors designed to investigate the determinants of common injuries, cardiovascular disease and cancer. While robust from an analytic perspective, the execution of prospective cohort studies in many settings is impeded by methodological, economic and organisational barriers. We examined the operational considerations of implementing a large-scale cohort study at a transfusion centre and evaluated measures taken to optimise data collection procedures. A pilot study of 1,000 participants revealed donor motivation to participate in this research was high (91% response rate). Comprehensive exposure data on lifestyle, behavioural and psychosocial factors were obtained from 95% of participants. Substantial heterogeneity in levels of potential risk factors was noted among respondents. Detailed dietary habit information and a study blood sample were obtained from 67% and 100% of participants, respectively. Study recruitment and baseline data collection was feasible during routine donor visits with minimal interruption to donor centre staff and procedures. We conclude the study design and characteristics of the regional donor program enhance the efficiency and significance of the proposed research.