BACKGROUND: Blood donation is safe, but a small proportion of donors have delayed and/or off-site reactions that have the potential to lead to serious injury. This retrospective study sought to identify risk factors for delayed reactions (DRs). STUDY DESIGN AND METHODS: The records of 793,293 allogeneic whole blood and apheresis donations in 2007 were assessed for vasovagal reactions. Donor demographic, biometric, and clinical measurements were captured. Incidents related to needle insertion and mild reactions were excluded. Based on the reaction onset time relative to the procedure end time, reactions were classified as delayed (>15 min) or immediate (≤15 min). Reactions were analyzed by multivariable logistic regression comparing donors with immediate reactions (IRs) or DRs to donors without reactions and comparing donors with DRs to IRs. The clinical consequences of off-site and on-site reactions are reported. RESULTS: The prevalence of reactions classified as moderate or severe was 41 in 10,000 donations; 24% of these reactions were delayed and 12% occurred off-site. DRs were associated with female sex (odds ratio [OR], 2.96; 95% confidence interval [CI], 2.21-3.96) and with low estimated blood volume (EBV; OR, 3.91; 96% CI, 2.84-5.51). Off-site reactions, particularly in female donors, were more likely to be associated with a fall, with head trauma, with other injury, and with the use of outside medical care. CONCLUSION: Low EBV, youth, and first-time donor status are major risk factors for IRs and DRs. Women are more likely than men to report DRs. Delayed and off-site reactions lead to potentially preventable morbidity. Understanding the physiologic basis of DRs may lead to the development of appropriate interventions to reduce their likelihood.