Background <p>This study examined whether appendectomy was associated with the subsequent risk of pneumonia/influenza and whether this association differed according to age at appendectomy. We also investigated whether modifiable risk-factor profiles were associated with variation in this observed association.</p> Methods <p>We conducted a prospective cohort study involving 404,577 participants from the UK Biobank. Participants with appendectomy were categorized into four groups according to age at surgery to evaluate age-specific associations. A weighted modifiable risk-factor score was constructed by summing six risk factors weighted by their corresponding regression coefficients, including smoking status, alcohol consumption, body mass index (BMI), ambient air pollution, physical activity, and diet. Participants with appendectomy were further categorized into quartiles of this score to assess whether the association between appendectomy and pneumonia/influenza differed across modifiable risk-factor profiles.</p> Results <p>During a median follow-up period of 13.8 years, a total of 27,589 pneumonia/influenza events were observed. Appendectomy was associated with a higher subsequent risk of pneumonia/influenza (hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 1.06–1.14). In the age-stratified analysis, compared with non-appendectomy participants, appendectomy performed at ages 10–20, 20–30, and ≥ 30 years was associated with higher risks of pneumonia/influenza, with HRs of 1.10 (95% CI: 1.04–1.15), 1.14 (95% CI: 1.06–1.22), and 1.14 (95% CI: 1.06–1.22), respectively, whereas no statistically significant association was observed for appendectomy performed before age 10 (HR: 1.01, 95% CI: 0.92–1.10). Among appendectomy participants, a more favorable modifiable risk-factor profile was associated with a lower risk of pneumonia/influenza. Participants in the lowest quartile of the weighted modifiable risk-factor score had a lower risk than participants without appendectomy (HR: 0.89, 95% CI: 0.82–0.96). These associations were consistent after propensity score matching (PSM).</p> Conclusion <p>Appendectomy was associated with a higher subsequent risk of pneumonia/influenza, particularly when performed after childhood. A favorable modifiable risk-factor profile was associated with attenuation of this observed association. From a public health perspective, appendectomy history and age at surgery may help identify individuals who could benefit from targeted respiratory infection prevention strategies, including smoking cessation, weight management, physical activity promotion, dietary improvement, promotion of vaccination, and reduction of environmental exposure.</p>