PURPOSE:Appendicitis is an inflammation of the appendix, the etiology of which is still poorly understood. Previous studies have shown an increased risk for cigarette smokers but no accounts for the timing of exposure to smoking relative to appendectomy were made. METHODS: Based on questionnaire data, both cohort and co-twin case-control analyses were conducted to assess the effect of active cigarette smoking on appendectomy in 3808 Australian twin pairs. Smoking status was defined as a time-dependent covariate to account for differences in timing of smoking initiation and onset of appendicitis. RESULTS: The questionnaire had a 65% pairwise response rate. After controlling for sex, age, and year of birth, appendectomy risk in current smokers was statistically significantly increased by 65% relative to never-smokers. This was largely unchanged by the duration or intensity of smoking and was not affected by socioeconomic status or father's occupation. The effect was stronger in females. Among former smokers, increased time since quitting significantly reduced the odds ratio of appendectomy by 15% for every year since quitting. CONCLUSION: After adjustment for age and other confounders, there was an increase in risk of appendectomy among current smokers relative to never-smokers, particularly in females. This study adds to the body of knowledge on the effects of tobacco smoking on the gastrointestinal tract.