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To determine the effect of 8-hydroxyquinoline (8HQ) on non-replicating Mycobacterium tuberculosis (Mtb) in comparison with its reported effect on replicating Mtb.The MIC of 8HQ for replicating H37Rv Mtb was determined by microdilution in 7H9 broth. Bactericidal activity was determined by exposing H37Rv Mtb to 8HQ for 4 days under conditions that otherwise allowed exponential replication (20% O2, pH 6.6) and conditions under which replication was precluded: 1% O2, pH 6.6; 20% O2, pH 5.5; or 20% O2, pH 5.5, 0.5 mM sodium nitrite. Serial dilutions were plated on 7H11 agar to quantify cfu. Frequency of resistance (FOR) was determined with >109 bacteria plated on 7H9 agar plates containing 2× MIC 8HQ.8HQ was active against replicating Mtb (MIC 2.5 µM, 0.36 mg/L). Under both replicating and non-replicating conditions, cfu were reduced in 4 days by ≥5 log10 at the highest concentration tested (10 µM). Bactericidal activity was maximal at low pH, where 8HQ reduced cfu by 1–1.5 log10 at 1 µM. We were unable to recover any 8HQ-resistant colonies.This study demonstrates that 8HQ has bactericidal activity of comparable potency against non-replicating and replicating Mtb, a property not observed for anti-infective agents currently approved for treatment of tuberculosis, and a very low FOR. Drugs with these properties are urgently needed to shorten the course of treatment for both active and latent tuberculosis.