Mycobacterium tuberculosis infection is associated with thrombocytosis. We sought to determine if this information might be valuable in evaluating granulomas using acid-fast stains (AFS). Fifty-eight patients with culture-confirmed M tuberculosis infection were compared with 75 patients with atypical mycobacterial infection and 48 patients negative for mycobacteria. Thrombocytosis (platelet count >360 × 10(3)/μL [360 × 10(9)/L]) was significantly more common in patients with M tuberculosis (50%) than those with either atypical mycobacterial infection (12%) or negative for mycobacteria (4%, P < .001 for each). In 67 patients, histologic evaluation of tissue samples showed granulomatous inflammation; 37 (55%) had positive AFS results. Of 19 patients with thrombocytosis, 16 (84%) had a positive AFS result compared with 21 (44%) of 48 without thrombocytosis (P = .003). Fifteen of 16 M tuberculosis cases with thrombocytosis had positive AFS findings on histologic evaluation; the single negative case had a platelet count of 362 × 10(3)/μL (362 × 10(9)/L). However, 3 of these cases of positive results on staining were initially diagnosed as negative and only recognized as positive on review. We conclude that patients whose specimens were sent for mycobacterial culture and thrombocytosis had an increased risk for M tuberculosis. Patients with granulomas and thrombocytosis are more likely to have a positive AFS result usually showing M tuberculosis. Finally, patients with initially negative AFS results and thrombocytosis deserve to have additional evaluation of the AFS specimens.