Background. The duration of infectiousness following pulmonary tuberculosis treatment initiation remains uncertain. We aimed to assess whether a bundled intervention designed to decrease respiratory exposure was feasible and would reduce new tuberculosis infections in household contacts (HHCs). Methods. We conducted a pilot cluster-randomized controlled trial with a hybrid type 1 effectiveness-implementation design in Santiago, Chile. Random allocation was performed, and 2 healthcare districts were assigned to the intervention (n = 180 HHCs) and 1 to standard of care (n = 149 HHCs). Eligible participants were people newly diagnosed with pulmonary tuberculosis and their HHCs. The intervention included education, mask use, household ventilation, and nightly separation of tuberculosis patients, for 2 weeks. Intervention adherence was evaluated weekly. Effectiveness was assessed at the individual level with QuantiFERON®-TB Gold Plus (QFT) test conversions in HHCs at 12-week follow-up. Results. Between October 2021 and December 2023, 384 HHCs and 157 people with tuberculosis were enrolled. Overall, 56.3% of contacts were women, with a mean age of 34.6 years and a baseline QFT positivity of 32.3%. A total of 216 contacts had negative QFT result at baseline, with 179 (82.9%) completing follow-up. QuantiFERON®-TB Gold Plus conversions occurred in 11 (12.8%) and 10 (10.8%) HHCs from the intervention and control arms, respectively (incidence risk ratio 1.10, 95% CI .71–1.71, P = .849). Good adherence to the respiratory bundle was reported by 53% of participants on day 7 and 54% on day 14. Conclusions. Isolation and restrictive measures after tuberculosis treatment initiation proved challenging and did not reduce tuberculosis infections in HHCs, suggesting limited benefit for transmission control.