To date there has been no satisfactory explanation of the worldwide excess of tuberculosis (TB) notifications among adult males. We investigated the epidemiological basis for sex differences in TB notifications in high-burden countries using available group-level data. Multiple linear regression analysis was used to explore the ecological relationship between smoking and sex differences in TB notifications among high-burden countries. Cigarette consumption was a significant predictor of the sex ratio of TB notifications, and explained 33% of the variance in the sex ratio of TB notifications. Our findings suggest that smoking is an important modifiable factor which has a significant impact on the global epidemiology of TB, and emphasize the importance of tobacco control in countries with a high incidence of TB. This analysis provides support for the interpretation of sex differences in worldwide TB notification rates as indicative of true differences in the epidemiology of TB between males and females.