Background <p>Recent studies suggest the rate of neoplasia in patients with complicated acute appendicitis initially managed nonoperatively is higher than previously reported.</p> Objective <p>This study aimed to determine the incidence and predictors of neoplasia in patients with complicated appendicitis treated nonoperatively.</p> Methods <p>We conducted a prospective cohort study of all patients who presented to a tertiary care center with acute appendicitis between 2019 and 2023. Patients with complicated appendicitis treated nonoperatively were included in the study cohort. Patient demographics, clinical course, radiological findings, and pathologic information were collected. The primary outcome was rate of neoplasia. Multivariable logistic regression analysis was performed to identify predictors of appendiceal neoplasia.</p> Results <p>In total, we identified 1166 patients with acute appendicitis, of whom 75 patients had complicated appendicitis treated nonoperatively (median age 51&#xa0;years [interquartile range 38–68]; 36 [48%] were female). Fifty-four (72%) patients had their appendix removed due to failure of nonoperative management, recurrent symptoms, suspicion of neoplasia, or elective surgery. The neoplasia rate among patients with complicated appendicitis initially treated nonoperatively was 16.0% (12/75). Two patients with neoplasia were younger than 40&#xa0;years of age. Suspicion of malignancy on initial imaging was associated with an increased risk of appendiceal neoplasia (odds ratio 8.13, 95% confidence interval 1.20–55.15; <i>p </i>= 0.03). Age, sex, and appendiceal diameter were not significantly associated with appendiceal neoplasia.</p> Conclusions <p>The high rate of appendiceal neoplasia in patients with complicated appendicitis treated nonoperatively should be a factor in decision making for interval appendectomy for patients of all ages.</p>