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Options for treatment of chronic spontaneous urticaria beyond antihistamines are limited. This multicenter, randomized, sham-controlled trial from 3 teaching hospitals in China compared acupuncture, sham acupuncture, and waitlist control for treatment of chronic spontaneous urticaria. Visual Abstract. Efficacy of Acupuncture for Chronic Spontaneous Urticaria: Options for treatment of chronic spontaneous urticaria beyond antihistamines are limited. This multicenter, randomized, sham-controlled trial from 3 teaching hospitals in China compared acupuncture, sham acupuncture, and waitlist control for treatment of chronic spontaneous urticaria. Background: The effectiveness of acupuncture for patients with chronic spontaneous urticaria (CSU), reported in a few small-scale studies, is not convincing. Objective: To investigate whether acupuncture leads to better effects on CSU than sham acupuncture or waitlist control. Design: A multicenter, randomized, sham-controlled trial. (Chinese Clinical Trial Registry: ChiCTR1900022994) Setting: Three teaching hospitals in China from 27 May 2019 to 30 July 2022. Participants: 330 participants diagnosed with CSU. Intervention: Participants were randomly assigned in a 1:1:1 ratio to receive acupuncture, sham acupuncture, or waitlist control over an 8-week study period (4 weeks for treatment and another 4 weeks for follow-up). Measurements: The primary outcome was the mean change from baseline in the Weekly Urticaria Activity Score (UAS7) at week 4. Secondary outcomes included itch severity scores, self-rated improvement, and Dermatology Life Quality Index scores. Results: The mean change in UAS7 (range, 0 to 42) for acupuncture from baseline (mean score, 23.5 [95% CI, 21.8 to 25.2]) to week 4 (mean score, 15.3 [CI, 13.6 to 16.9]) was −8.2 (CI, −9.9 to −6.6). The mean changes in UAS7 for sham acupuncture and waitlist control from baseline (mean scores, 21.9 [CI, 20.2 to 23.6] and 22.1 [CI, 20.4 to 23.8], respectively) to week 4 (mean scores, 17.8 [CI, 16.1 to 19.5] and 20.0 [CI, 18.3 to 21.6], respectively) were −4.1 (CI, −5.8 to −2.4) and −2.2 (CI, −3.8 to −0.5), respectively. The mean differences between acupuncture and sham acupuncture and waitlist control were −4.1 (CI, −6.5 to −1.8) and −6.1 (CI, −8.4 to −3.7), respectively, which did not meet the threshold for minimal clinically important difference. Fifteen participants (13.6%) in the acupuncture group and none in the other groups reported adverse events. Adverse events were mild or transient. Limitation: Lack of complete blinding, self-reported outcomes, limited generalizability because antihistamine use was disallowed, and short follow-up period. Conclusion: Compared with sham acupuncture and waitlist control, acupuncture produced a greater improvement in UAS7, although the difference from control was not clinically significant. Increased adverse events were mild or transient. Primary Funding Source: The National Key R&D Program of China and the Science and Technology Department of Sichuan Province. [ABSTRACT FROM AUTHOR]