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Background This updated systematic review and meta-analysis investigates the putative role of the appendix in ulcerative colitis as a therapeutic target. Methods Ovid Medline, Embase, PubMed and CENTRAL were searched with MeSH terms (“appendectomy” OR “appendicitis” OR “appendix”) AND (“colitis, ulcerative”) through October 2020, producing 1469 references. Thirty studies, including 118 733 patients, were included for qualitative synthesis and 11 for quantitative synthesis. Subgroup analysis was performed on timing of appendicectomy. Results are expressed as odds ratio (OR) with 95% confidence intervals (CIs). Results Appendicectomy before UC diagnosis reduces the risk of future colectomy (OR, 0.76; 95% CI, 0.65-0.89; I2 = 5%; P = .0009). Corresponding increased risk of colorectal cancer and high-grade dysplasia are identified (OR, 2.27; 95% CI, 1.11-4.66; P = .02). Significance is lost when appendicectomy is performed after disease onset. Appendicectomy does not affect hospital admission rates (OR, 0.87; 95% CI, 0.68-1.12; I2 = 93%; P = .27), steroid use (OR, 1.08; 95% CI, 0.78-1.49; I2 = 36%; P = .64), immunomodulator use (OR, 1.04; 95% CI, 0.76-1.42; I2 = 19%; P = .79), or biological therapy use (OR, 0.76; 95% CI, 0.44-1.30; I2 = 0%; P = .32). Disease extent and risk of proximal progression are unaffected by appendicectomy. The majority (71% to 100%) of patients with refractory UC avoid colectomy following therapeutic appendicectomy at 3-year follow-up. Conclusions Prior appendicectomy reduces risk of future colectomy. A reciprocal increased risk of CRC/HGD may be due to prolonged exposure to subclinical colonic inflammation. The results warrant further research, as consideration may be put toward incorporating a history of appendicectomy into IBD surveillance guidelines. A potential role for therapeutic appendicectomy in refractory left-sided UC is also identified.