Appendectomy is a frequently performed surgical procedure; however, long-term consequences have not been fully explored. We used a nationwide population-based cohort to determine whether patients undergoing appendectomy are at an increased risk of sepsis. Overall, 252,688 patients undergoing appendectomy and 252,472 matched controls were identified from the National Health Insurance Research Database in Taiwan. A propensity score analysis was used for matching age, sex, index year and comorbidities at a ratio of 1:1. Multiple Cox regression and stratified analyses were used to estimate the adjusted hazard ratio (aHR) of developing sepsis. Patients undergoing appendectomy had a 1.29 times (aHR: 1.29; 95% confidence interval [CI], 1.26-1.33) higher risk of developing sepsis than those not undergoing. Patients aged 20-49 years had a 1.58-fold higher risk of sepsis in the appendectomy cohort (aHR; 95% CI, 1.50-1.68). Also, having undergone appendectomy, patients had a higher likelihood of sepsis, regardless of sex and with or without comorbidities. Patients with <1 year follow-up showed a 1.98-fold risk of sepsis in the appendectomy cohort. Patients with 1-4 and ≥5 years follow-up showed a 1.29 and 1.11-fold risk of sepsis, respectively. Future research is required to elucidate the possible immuno-pathological mechanisms of these associations.