Background: Sputum samples from patients with non-multidrug-resistant (non-MDR) pulmonary TB may remain smear-positive for acid-fast bacilli (AFB) at the fifth month of anti-TB treatment. However, its significance remains unknown. Methods: From January 2004 to April 2009, there were 5,403 patients with culture-confirmed pulmonary TB from four hospitals in Taiwan. Among them, 116 patients (2.2%) with non-MDR TB whose sputum samples were smear-positive by concentration smear method at the fifth month of treatment were evaluated. Results: Sputum culture yielded Mycobacterium tuberculosis in 10 patients (8.6%, MTB group), nontuberculous mycobacteria in 23(19.8%, NTM group), and no growth in the remaining 83 (71.6%, no-growth group). The relapse rate (22%) was higher in the MTB group (P = .01). Four predictors, smear grading >= 3+ at the fifth month ("S") (OR, 10.73; 95% CI, 2.67-43.17), no sputum culture conversion on the second month ("C") (OR, 7.16; 95% CI, 1.45-35.44), lack of directly observed therapy ("O") (OR, 6.40; 95% CI, 1.54-26.56), and no radiographic improvement at the fifth month ("R") (OR, 4.18; 95% CI, 1.02-17.10), were associated with viable M tuberculosis (MTB group). An integrated "SCOR" index of 1 point for each positive factor had the best discriminatory power for predicting culture results at the fifth month. If the SCOR index was 0, all smear-positive sputum was culture-negative for M tuberculosis. Conclusions: Positive sputum smears by a concentrated smear method at the fifth month of treatment in patients with non-MDR TB, especially those with a low SCOR index, may be due to nonviable bacilli and NTM. Careful review of the quality of patient supervision, bacteriologic data, and chest radiography is crucial.