Background: Postprandial distress syndrome (PDS) is the most common subtype of functional dyspepsia. Acupuncture is commonly used to treat PDS, but its effect is uncertain because of the poor quality of prior studies. Objective: To assess the efficacy of acupuncture versus sham acupuncture in patients with PDS. Design: Multicenter, 2-group, randomized clinical trial. (ISRCTN registry number: ISRCTN12511434) Setting: 5 tertiary hospitals in China. Participants: Chinese patients aged 18 to 65 years meeting Rome IV criteria for PDS. Intervention: 12 sessions of acupuncture or sham acupuncture over 4 weeks. Measurements: The 2 primary outcomes were the response rate based on overall treatment effect and the elimination rate of all 3 cardinal symptoms: postprandial fullness, upper abdominal bloating, and early satiation after 4 weeks of treatment. Participants were followed until week 16. Results: Among the 278 randomly assigned participants, 228 (82%) completed outcome measurements at week 16. The esti-mated response rate from generalized linear mixed models at week 4 was 83.0% in the acupuncture group versus 51.6% in the sham acupuncture group (difference, 31.4 percentage points [95% CI, 20.3 to 42.5 percentage points]; P < 0.001). The estimated elimination rate of all 3 cardinal symptoms was 27.8% in the acupuncture group versus 17.3% in the sham acupuncture group (difference, 10.5 percentage points [CI, 0.08 to 20.9 percentage points]; P = 0.034). The efficacy of acupuncture was maintained during the 12-week posttreatment follow-up. There were no serious adverse events. Limitation: Lack of objective outcomes and daily measurement, high dropout rate, and inability to blind acupuncturists. Conclusion: Among patients with PDS, acupuncture resulted in increased response rate and elimination rate of all 3 cardinal symptoms compared with sham acupuncture, with sustained efficacy over 12 weeks in patients who received thrice-weekly acupuncture for 4 weeks.