Fluoroquinolone monotherapy for community-acquired pneumonia has been associated with early improvement of symptoms in tuberculosis-infected patients and subsequent delay in its diagnosis and treatment. We hypothesize that a short course of fluoroquinolone therapy can increase the acid-fast bacillus (AFB) smear-negative rate of pulmonary tuberculosis and delay its culture growth. A cohort study was conducted with 68 patients whose respiratory cultures tested positive for Mycobacterium tuberculosis and were divided into 2 groups. The first group, named the fluoroquinolone-treated group (FQT), consisted of patients who received fluoroquinolone before respiratory specimen collection (29%). The control group consisted of patients who were treated with a nonfluoroquinolone antibiotic and patients who did not receive antibiotics (71%). These groups were subdivided into the symptomatic subgroup (patients with respiratory symptoms) and the asymptomatic subgroup (patients with nonrespiratory symptoms). The AFB smears were negative in 55% of the FQT patients and 33% of the control patients (relative risk, 1.65; P = 0.111). The symptomatic FQT subgroup had an AFB smear-negative rate of 56% as compared with 18% of the symptomatic control subgroup (relative risk, 3.056; P = 0.0107). In the symptomatic subpopulation, the corresponding FQT subgroup had a median number of 44 days to culture growth and the control subgroup had 24.5 days to culture growth (P = 0.044). In conclusion, a brief course of empiric fluoroquinolone monotherapy can increase the AFB smear-negative rate of respiratory secretions and delay the M. tuberculosis culture growth of patients with symptomatic tuberculosis who were treated empirically for community-acquired pneumonia.