This study investigated whether there was an association between splenectomy and pulmonary tuberculosis. This was a case-control study using the database of the Taiwan National Health Insurance Programme. We identified 18 960 patients (aged 20 years or older) with newly diagnosed pulmonary tuberculosis as the case group and 73 988 participants without pulmonary tuberculosis as the control group from 1998 to 2011. Both groups were matched for sex, age (per 5 years) and index year of pulmonary tuberculosis diagnosis. The risk of pulmonary tuberculosis associated with splenectomy and other co-morbidities was estimated. After controlling for confounders, multivariable logistic regression analysis showed that the odds of pulmonary tuberculosis were 1.91 in patients with splenectomy (95% CI 1.06-3.44), compared with the participants without splenectomy. Chronic obstructive pulmonary diseases (OR 3.07, 95% CI 2.94-3.21), pneumoconiosis (OR 2.20, 95% CI 1.90-2.56), chronic kidney diseases (OR 1.49, 95% CI 1.33-1.67), diabetes mellitus (OR 1.57, 95% CI 1.50-1.64) and chronic liver diseases (OR 1.31, 95% CI 1.25-1.37) were associated with an increased risk of pulmonary tuberculosis. The sub-analysis demonstrated that the odds of pulmonary tuberculosis were 4.81 (95% CI 2.31-10.0) for patients co-morbid with splenectomy and any of the above diseases. Splenectomy is associated with a 1.9-fold increased risk of pulmonary tuberculosis in Taiwan. There is a synergistic effect between splenectomy and other co-morbidities on the risk of pulmonary tuberculosis.