BACKGROUND: Tuberculosis preventive treatment (TPT) is essential for the end TB Strategy, but shorter and better tolerated regimens are needed to boost its coverage and acceptance. METHODS: Silicosis patients aged 18 to 65 years received a novel 1H3P3 regimen (400 mg isoniazid and 450 mg rifapentine, thrice-weekly for 4 weeks) under direct observation and were actively followed up for 3 years. The safety and efficacy were compared to the 3-month, once-weekly isoniazid/rifapentine (3HP) group and observation group from our previous trials. RESULTS: A total of 279 eligible participants were enrolled, and 238 participants provided informed consent. All eligible participants had a median age of 56 years (IQR 52-60), 163 (68.5%) participants had a Bacillus Calmette-Guerin vaccine scar, and 74 (31.1%) participants were QuantiFERON-TB Gold In-Tube positive. There were 88 adverse events from 66 (27.7%) participants and only one (0.4%) participant had a Grade 3 adverse event. The completion rate was 92.0% (219/238). Six (2.5%) participants were diagnosed with active TB, five of which were bacterial confirmed cases. The cumulative active TB rate was 1.67 cases per 100 person-years. Compared to the previous study, the 1H3P3 regimen significantly reduced the 3-year cumulative active TB rate than the observation group (HR = 0.26, Log-rank CONCLUSION: The 1H