The Ultra-Curto study compared one month of daily rifapentine and isoniazid treatment (1HP) with three months of weekly treatment (3HP) for the prevention of tuberculosis in HIV-negative adolescents and adults who tested positive for latent tuberculosis after recent exposure in Brazil. 500 individuals were randomized (249 to 1HP, 251 to 3HP), of which 193 men and 307 women with a median age of 39 years. Successful completion of treatment (>90% of medication) was 89.6% in 1HP versus 84.1% in 3HP (risk difference 5.2%, 95% CI: -0.1% to 11.2%, p=0.10). Targeted grade >2 adverse events or treatment discontinuation occurred in 16.1% of 1HP and 10.4% of 3HP recipients (risk difference 6.1%, 95% CI: -0.04% to 12.3%, p=0.05). Discontinuation rates for any side effect were 7.2% for 1HP and 4.4% for 3HP. After adjustment for covariates, the difference in the primary safety outcome was 3.4% (95% CI: -2.3% to 9.1%, p=0.24). Both regimens had a high success rate, with 1HP showing more targeted safety events, mostly of low grade, with no predominance of one over the other.