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Background Side-effect concerns are a major barrier to vaccination against COVID-19 and other diseases. Identifying cost- and time-efficient interventions to improve vaccine experience and reduce vaccine hesitancy—without withholding information about side effects—is critical. Purpose Determine whether a brief symptom as positive signals mindset intervention can improve vaccine experience and reduce vaccine hesitancy after the COVID-19 vaccination. Methods English-speaking adults (18+) were recruited during the 15-min wait period after receiving their second dose of the Pfizer COVID-19 vaccination and were randomly allocated to the symptom as positive signals mindset condition or the treatment as usual control. Participants in the mindset intervention viewed a 3:43-min video explaining how the body responds to vaccinations and how common side effects such as fatigue, sore arm, and fever are signs that the vaccination is helping the body boost immunity. The control group received standard vaccination center information. Results Mindset participants (N = 260) versus controls (N = 268) reported significantly less worry about symptoms at day 3 [ t (506)=2.60, p =.01, d =0.23], fewer symptoms immediately following the vaccine [ t (484)=2.75, p =.006, d =0.24], and increased intentions to vaccinate against viruses like COVID-19 in the future [ t (514)=−2.57, p =.01, d =0.22]. No significant differences for side-effect frequency at day 3, coping, or impact. Conclusions This study supports the use of a brief video aimed at reframing symptoms as positive signals to reduce worry and increase future vaccine intentions. Clinical Trial information Australian New Zealand Clinical Trials Registry: ACTRN12621000722897p. [ABSTRACT FROM AUTHOR]