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Purpose: Acute appendicitis (AA) is frequent, its diagnosis is challenging, and the surgical intervention is not risk free. An accurate diagnosis will reduce unnecessary surgeries and associated risks. This study aimed to analyze the rate of appendectomies' postoperative complications. Methods: Multicenter, prospective, observational study conducted at three large hospitals (Pisa University Hospital, Italy; Henri Mondor University Hospital, Paris, France; and Valencia University Hospital, Spain). Results: A total of 3070 patients with a median age of 28 years (IQR 20–43) were enrolled. 1403 (45.7%) were females. Eight hundred ninety patients (29%) did not undergo preoperative imaging. Ultrasound and CT scans were performed in 1465 (47.7%) and 715 (23.3%) patients. Patients requiring CT scan were older [median 38 (IQR 26–53) vs. no imaging median 24 (IQR 16–35), Ultrasound median 28 (IQR 20–41); p < 0.0001]. Laparoscopic appendectomy was performed in 58.6%. Complications developed in 1279 (41.7%) patients: Clavien–Dindo grades I–II in 1126 (33.9%); Clavien–Dindo grades III–IV in 146 (5.2%). Overall mortality was 0.2%. Following resection of a normal appendix, 15% experienced major complications (Clavien–Dindo grades IIIb and above). Multivariable analysis revealed that age, Charlson comorbidity index, histopathology, and Alvarado score over 7 were associated with a higher risk of Clavien–Dindo complication grades IIIa and higher. Conclusion: Appendectomy may be associated with serious postoperative complications. Complications were associated with older age, Charlson comorbidity index, histopathology, and high Alvarado scores. The definition of accurate diagnostic and therapeutic pathways may improve results. The association between clinical scores and radiology is recommended. [ABSTRACT FROM AUTHOR]