Sensitivity and specificity estimates for 18 skeletal lesions were generated from modern skeletons for future paleoepidemiological analyses of tuberculosis prevalence in archaeological samples. A case-control study was conducted using 480 skeletons from 20th century American skeletal collections. One-half of the skeletons were documented tuberculosis cases (Terry Collection). The remaining age and sex-matched skeletons were controls (Bass Collection). The association between 18 candidate skeletal lesions and tuberculosis was established by comparing lesion distributions in case and control groups. Lesion indicators at six locations – visceral surface of ribs, ventral vertebral bodies, lateral part of ilium, acetabular fossa, iliac auricular surface, and ulna olecranon process - occurred significantly more often among cases than in controls, and were associated with one another. The most useful indicator proved to be a bony reaction on ventral thoracic and lumbar vertebral bodies. Its presence means a 53.3% probability of a true tuberculosis diagnosis. Because of the nature of the reference sample – 20th century American cases – sensitivity and specificity estimates will better estimate disease prevalence in archaeological samples from cultural settings where pulmonary tuberculosis predominated. The general approach of this proof-of-concept study is applicable to other diseases that occur commonly and affect bone.