Tuberculosis reactivation is a serious threat in patients treated with anti-tumour necrosis factor therapy. A 6-month regimen with isoniazid is considered as the standard of care, but patient adherence is a major shortcoming. We carried out an open-label, single-arm intervention study to assess the efficacy, the completion rate and the tolerability of a 3-month regimen with isoniazid plus rifampin. Seventy-eight patients with rheumatic conditions proposed for anti-tumour necrosis factor (TNF) therapy and at risk of tuberculosis reactivation were offered to participate in the study. Nine patients were excluded due to deficit of glucose-6-phosphate dehydrogenase (n = 1), salicylate hypersensitivity (n = 1), declining to participate (n = 5) or preferring a 6-month isoniazid regimen (n = 6). Sixty-nine patients were treated with a 3-month regimen with isoniazid and rifampin. No cases of tuberculosis were observed after a mean follow-up of 90 months (range from 66 to 121 months). Sixty (87 %) patients completed the therapy. Nine (13 %) patients discontinued the therapy due to rifampin hypersensitivity (n = 1), symptomatic grade 3-4 hepatotoxicity (n = 2), abdominal discomfort (n = 2), pruritus (n = 1), arthritis (n = 1) and personal concerns (n = 2). A short course treatment with isoniazid and rifampin provided efficacy, good tolerability and good completion rate in patients with rheumatic conditions proposed for anti-TNF therapy.