Background: Complications of donation reduce donor return. Younger and less experienced donors are more likely to experience vasovagal-type reactions (VVR). A water drink of approximately 500 mL shortly before donation may reduce VVR, but the effect of a smaller volume of water has not been investigated. Study design and methods: A placebo-controlled comparative study was conducted among donors < 30 years who attended for a 1st-4th whole blood (WB) donation. Collection centers were assigned to offer one of three interventions: 500 mL water drink, 330 mL water drink, or a placebo intervention consisting of pre-donation arm exercise. Within 7 days after attending, participants received an electronic questionnaire about possible symptoms during and after donation. In additional centers, control donors were recruited, who only received standard care and were also sent the questionnaire. Self-reported VVR and other complications were evaluated in all groups. Results: Out of 8,300 participating donors, 6,921 (83%) returned the questionnaire. Overall, 18.5% of responding donors reported moderate or worse VVR symptoms. In 2nd-4th time donors, both water volumes decreased the odds of a VVR compared to standard care controls (OR500ml 0.75, 95% CI 0.59-0.94; OR330ml 0.73, 0.58-0.91; adjusted combined OR 0.77, 0.64-0.94). There was no effect in new donors or the placebo group compared to controls. Conclusion: In young donors making their 2nd-4th WB donation, drinking water was associated with 23% fewer VVR with no difference between 330 and 500 mL. This decrease was not found in the placebo group. The findings support advocating drinking water for the prevention of VVR.