Comorbidity has been proven to increase hospital costs and length of hospital stays in patients receiving appendectomy for the treatment of acute appendicitis. However, the specific comorbidities that independently influence discrepancy of hospital costs and length of stay between open appendectomy and laparoscopic appendectomy still need to be elucidated. Using multivariate linear analysis, administrative claims data were obtained from Taiwan's National Health Institute Research Database to compare differences of hospitalization costs and length of stay between open appendectomy and laparoscopic appendectomy categorized by various comorbidities defined in Charlson comorbidity score. Of 103,653 patients, 81,479 open appendectomies and 22,174 laparoscopic appendectomies were performed for the treatment of acute appendicitis in Taiwan between 2004 and 2008. In multilinear regression models, the adjusted costs and length of stay for open appendectomy in patients with cerebrovascular diseases or diabetes mellitus were significantly higher than that for laparoscopic appendectomy. To reduce costs and length of stay, patients with cerebrovascular diseases or diabetes mellitus should be particularly recommended to receive laparoscopic approach rather than an open approach for the treatment of acute appendicitis.