Background/Aims: According to the Chicago classification version 3.0, high-resolution manometry (HRM) should be performed in the supine position. However, with the patient in the upright/sitting position, the test could more closely simulate real-life behavior and may be better tolerated. We performed a systematic review of the literature to search whether the manometric variables and the final diagnosis are affected by positional changes. Methods: A literature search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Studies published in English that compared HRM results in different body positions were included. Moreover, the change in diagnosis of esophageal motility disorders according to the shift of body position was investigated. Results: Seventeen studies including 1714 patients and healthy volunteers met the inclusion criteria. Six studies showed a significant increase in lower esophageal sphincter basal pressure in the supine position. Integrated relaxation pressure was significantly higher in the supine position in 10 of 13 studies. Distal contractile index was higher in the supine position in 9 out of 10 studies. One hundred and fifty-one patients (16.4%) out of 922 with normal HRM in the supine position were diagnosed with ineffective esophageal motility (IEM) when the test was performed in the upright position (P < 0.001). Conclusions Performing HRM in the upright position affects some variables and may change the final manometric diagnosis. Further studies to determine the normal values in the sitting position are needed.