The usefulness of IFN-gamma release assays to monitor the efficacy of anti-tuberculosis (TB) treatment is controversial. Sixty patients affected by culture-confirmed pulmonary TB (M = 36; mean age: 39.2 yr; Italians = 28) were serially tested in a low prevalence setting by means of QuantiFERON-TB GOLD In-Tube (QFT-IT) at baseline and after a successful six-month therapy regimen (T6). A sub-group of 40 cases was also tested at 1 and 3 months. Overall, 88.3% of patients scored a QFT-IT positive result at baseline, with the higher proportion of TB-specific IFN-gamma responses in foreign-born patients (p = 0.04). TB-specific responses were highly variable over time, the within-person variability being correlated with baseline IFN-gamma levels (r = 0.731; p < 0.001). Overall, 61.6% of cases still tested QFT-IT positive at the completion of therapy. Average IFN-gamma levels increased over time, being persistently significantly higher in Italian patients than in foreign-born cases both at baseline (p = 0.03) and at T6 (p = 0.02). Reversion mainly occurred in patients (26.6%) with baseline IFN-gamma levels close to the conventional cut-off value. No indeterminate results were recorded at any study time point. In conclusion, QFT-IT adds no significant information to clinicians for treatment monitoring when applied in routine clinical practice in a low prevalence setting. Kinetics of T cell responses upon TB treatment and reversion (and conversion) thresholds need to be addressed. Diversity of IFN-gamma responses among patients of different geographic origin is an issue to be investigated further.