To determine the rate of true tuberculin skin test (TST) response in a cohort of patients with rheumatic disease treated with tumor necrosis factor inhibitors (TNFi). The study population included consecutive patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) treated with TNFi for at least 3 months. Patients with a positive TST at screening who began Tb prophylaxis before the beginning of TNFi therapy were excluded. All patients underwent a second TST. True TST response was defined as an increase of 6 mm of induration between the screening test and the second test. Forty patients (12 men and 28 women) were included. Mean age was 51.2 years. Of them, 27 (67.5%) had RA, eight (20%) had PsA, and five patients (12.5%) had AS. At pre-treatment TST, 15 patients had a TST > or = 5 mm. A significantly higher percent of patients with TST > or = 5 mm was seen among men compared with women (75% vs. 21%, p = 0.012) and patients with PsA compared with patients with RA (75% vs. 22%, p = 0.014). At the second test, eight (20%) had an increase of 6 mm between readings with four having an increase of 10 mm or more. Four patients received infliximab and the other four were treated with etanercept. Seven of these eight patients had RA and one was a patient with PsA. Patients with true TST response were significantly older and non-smokers with elevated sedimentation rate and a higher rate of anemia. Nationality, comorbid conditions, treatment with immunosuppressives, and BCG vaccination status had no significant influence on the TST response. Serial TST testing in patients receiving TNFi is indicated to identify patients with reactivation of latent tuberculosis infection or those exposed to mycobacterium.