The increased risk to patients on anti–tumor necrosis factor-alfa therapy of developing active tuberculosis supports screening of these patients for latent tuberculosis infection. The current practice of determining the presence of latent tuberculosis infection primarily, and often entirely, depends on the use of tuberculin skin testing (TST). We report a patient with psoriasis on long-term etanercept therapy who had a negative TST result and a positive interferon-gamma release assay result. Similar cases have also been found through a review of the literature. These findings suggest that TST might be unreliable during long-term anti–tumor necrosis factor-alfa therapy. QuantiFeron-TB Gold testing may be a more appropriate primary test in patients with risk factors for false-negative TST results.