BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is characterized by symptoms of orthostatic intolerance and is frequently observed in post-COVID conditions. OBJECTIVES: We conducted controlled, prospective, and randomized clinical trials to explore the potential therapeutic benefits of low-level tragus stimulation (LL-TS) in patients with POTS following COVID-19 infection. METHODS: This study enrolled 57 participants with confirmed post-acute COVID-19 who had been diagnosed with POTS. The ear clip was attached to the right tragus of the patients for stimulation (20 Hz with a 1-ms duration) or sham stimulation. They were divided into two groups: the sham LL-TS group (sham stimulation, n = 26) and the LL-TS group (stimulation for 1 month, n = 31). LL-TS was performed 1 h twice daily for 1 month. Postural tachycardia was evaluated at baseline, 1-month visit, and 1-year visit. Heart rate variability (HRV) and plasma neuropeptide Y (NPY) were evaluated at respective time points. RESULTS: The mean age of participants was 31.9 ± 7.2 years (61.4% female). LL-TS significantly attenuated the increase in heart rate from supine to a 10-min stand, as well as the average and maximum heart rates after 1 month of treatment. LL-TS also significantly reduced NPY levels. In addition, LL-TS significantly increased the high frequency (HF), but decreased the low frequency (LF) and LF/HF ratio during the postural test (all p <
0.01). These effects persisted during the 1-year follow-up. CONCLUSION: LL-TS may be a promising therapeutic approach for attenuating autonomic imbalance in patients with POTS following COVID-19 infection.