Associations between human leukocyte antigen (HLA) and postural orthostatic tachycardia syndrome (POTS) have not been investigated. We included patients diagnosed with POTS and showing orthostatic heart rate increases ≥ 50 during orthostatic vital sign measurement or experiencing syncope/near-syncope while standing (prominent POTS; n = 17). DQB1*06:09 was present in seven (41%) patients, a significantly higher percentage than in healthy Koreans (7%; odds ratio [OR] 8.7, 95% confidence interval [CI] 3.1-24.3, corrected P = 3.2 × 10-4) and epilepsy controls (8%; OR 7.9, 95% CI 2.7-23.5, corrected P = 3.2 × 10-4). Six (35.3%) carried the A*33:03-B*58:01-C*03:02-DRB1*13:02-DQB1*06:09 haplotype. The results signify an autoimmune etiology in prominent POTS.