Studies of the relationship between antibiotic use and resistance in pneumococci have produced conflicting results, reflecting differences in study design, setting, and measures of association used. Mathematical models of pneumococcal transmission dynamics provide a framework for interpreting and reconciling these studies. The model predicts, and the review of published studies confirms, that treatment often has little effect in increasing an individual's absolute risk of carrying/being infected by penicillin-resistant Streptococcus pneumoniae (PRSP). However, treatment substantially increases a patient's risk of carriage of/infection by PRSP relative to that of penicillin-susceptible S. pneumoniae (PSSP). The appropriate measure of association depends on the question of interest. Antibiotic use can substantially increase the prevalence of risk in the community as a whole, even when there is a small or nonexistent effect of treatment on the absolute risk that a treated individual will carry a resistant organism. Recommendations for the design and analysis of future studies of antibiotic treatment and pneumococcal resistance are proposed.