BACKGROUND: Vasovagal reactions (VVRs) have a negative impact on donor safety and return. Applied muscle tension (AMT) increases blood pressure temporarily and has been suggested as a way to reduce donors' risk of VVRs. This study evaluated whether using AMT at three different time points during the donation procedure reduces the VVR symptoms reported by donors and the VVR reactions recorded by phlebotomists. STUDY DESIGN AND METHODS: A three-arm, multicenter, open-label randomized controlled trial was used to compare VVR symptoms and reaction rates between those practicing AMT during the entire donation (n = 244) to practicing AMT at VVR high-risk time points (n = 250) to a standard blood donation control group (n = 240). All participants were asked to drink 500 mL of water in the waiting area, and an even distribution of new and repeat donors was sought across conditions. RESULTS: Across all conditions, donors reported few VVR symptoms and the rate of reporting did not differ significantly across conditions. However, donors who practiced AMT at strategic time points had a significantly lower number of phlebotomist-registered VVRs in comparison to the other two study groups, with these rates not varying by sex or donor status. Greater compliance by donors with AMT instructions was observed in those asked to practice AMT at strategic time points compared to those asked to practice AMT during the entire donation. CONCLUSION: Practicing AMT at VVR high-risk time points reduces the number of phlebotomist-registered VVRs.