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• Quantitative changes in QuantiFERON-TB Gold (QFT) response do not stratify tuberculosis (TB) risk in QFT-positive contacts. • QFT conversion after 3 months identifies contacts at significantly increased TB risk. • QFT conversion is associated with exposure to rapidly progressive pulmonary TB. • Pre-existing latent TB infection may protect against developing TB following re-exposure. We investigated whether quantifying the serial QuantiFERON-TB Gold (QFT) response improves tuberculosis (TB) risk stratification in pulmonary TB (PTB) contacts. A total of 297 untreated adult household PTB contacts, QFT tested at baseline and 3 months after index notification, were prospectively observed (median 1460 days). Normal variance of serial QFT responses was established in 46 extrapulmonary TB contacts. This informed categorisation of the response in QFT-positive PTB contacts as converters, persistently QFT-positive with significant increase (PP increase), and without significant increase (PP no-increase). In total, eight co-prevalent TB (disease ≤3 months after index notification) and 12 incident TB (>3 months after index notification) cases were diagnosed. Genetic linkage to the index strain was confirmed in all culture-positive progressors. The cumulative 2-year incident TB risk in QFT-positive contacts was 8.4% (95% confidence interval, 3.0-13.6%); stratifying by serial QFT response, significantly higher risk was observed in QFT converters (28%), compared with PP no-increase (4.8%) and PP increase (3.7%). Converters were characterised by exposure to index cases with a shorter interval from symptom onset to diagnosis (median reduction 50.0 days, P = 0.013). QFT conversion, rather than quantitative changes of a persistently positive serial QFT response, is associated with greater TB risk and exposure to rapidly progressive TB. [ABSTRACT FROM AUTHOR]