BACKGROUND: Vasovagal reactions (VVRs; faintness or fainting) can harm donor health and retention. Higher VVR rates are often observed in first-time donors and donors with VVR histories. We quantified associations between donation history (including donation experience, donation frequency, and VVR history) and VVR symptom reports in donors in England and assessed their mediation by venipuncture pain and donation anxiety. METHODS: In 60,026 STRIDES BioResource study participants recruited from 2019 to 2022, donation history was obtained from blood service records, while venipuncture pain, donation anxiety, and VVR symptoms were reported via post-donation questionnaires. We conducted causal mediation analyses estimating risk ratios (RRs) for indirect effects of donation history on VVR symptom reports through pain and anxiety while quantifying exposure-mediator interaction. RESULTS: Adjusted RRs for VVR symptoms were 1.24 (95% confidence interval: 1.19, 1.30) for newer/lapsed donors, 1.19 (1.13, 1.25) for less frequent donors, and 1.82 (1.71, 1.94) for donors with VVR histories. Pain and anxiety were associated with up to 1.28 and 1.60 times the risk of symptom reporting. Anxiety mediated 19.0% and 11.2% of associations with donation experience and frequency, whereas pain mediated no associations. Associations of pain and anxiety with VVR symptoms were only observed among donors without, not with, VVR histories. DISCUSSION: Our findings suggest that differences in venipuncture pain and donation anxiety do not primarily explain differences in VVR symptoms by blood donation history. While intervening on pain and anxiety may fail to equalize symptom disparities linked to donation history, interventions may reduce VVR burden in donors without VVR histories.