Background: No randomised controlled trial (RCT) has previously evaluated the effect of antitubercular therapy (ATT) in patients with uveitis of undetermined cause who tested positive on interferon-gamma release assays (IGRA), despite the absence of other identifiable causes of uveitis. We aimed to assess the efficacy and safety of treatment involving ATT compared to treatment without ATT in these patients, with respect to uveitis resolution and reduction in the risk of relapse. Methods: We conducted a single-blind, single-centre, phase 2 RCT at the uveitis clinic of Cipto Mangunkusumo Hospital in Jakarta, Indonesia, from August 16, 2021, to February 5, 2024. Seventy-six adults with newly diagnosed, active uveitis of undetermined cause and a positive IGRA were randomised 1:1 using block randomisation (block size 4) into two groups. Participants in the ATT group received an additional full course of ATT in addition to systemic corticosteroids. The control group received systemic corticosteroids without ATT. Investigators were masked to group assignment. The primary endpoint was the complete resolution of uveitis six months after randomisation. The trial is registered atClinicalTrials.gov(NCT05005637). Findings: Seventy-six participants were randomly assigned to either ATT (n = 37) or control (n = 39) group. At primary end point, more participants assigned to the ATT group achieved the primary outcome of complete uveitis resolution compared to the control group (30/37, 81.1% vs. 20/39 participants; 51.3%, relative risk [RR] 1.58, 95% CI 1.12–2.23, p = 0.0060). Over the subsequent follow-up period, complete uveitis resolution was observed in 34 and 24 participants assigned to the ATT and the control groups, respectively. Additionally, uveitis relapse occurred in fewer participants assigned to the ATT group compared to those assigned to the control group (2/34 participants, 5.9% vs. 7/24 participants, 29.2%; HR 0.20, 95% CI 0.05–0.89, p = 0.0210). The findings regarding uveitis resolution and relapse rates were consistent in the per-protocol analysis. Interpretation: In IGRA-positive patients with uveitis of undetermined cause, initial treatment with ATT resulted in a significant benefit over those not receiving ATT. Funding: This work was supported by RISPRO-LPDP (Riset Inovatif Produktif—Lembaga Pengelola Dana Pendidikan). © 2025 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/