Our aim was to analyze the performance of an interferon-gamma release assay, QuantiFERON-TB Gold (QFT-2G), for diagnosing Mycobacterium tuberculosis (MTB) infection in patients with systemic lupus erythematosus (SLE). We performed the QFT-2G and tuberculin skin test (TST) in 71 SLE patients. The QFT-2G results of 279 patients with other connective tissue diseases (CTD) and 35 healthy controls were analyzed. Of the 71 SLE patients, two (2.8%) were positive and 46 (64.8%) were negative by QFT-2G. All SLE patients had no evidence of active MTB infection, apart from one. QFT-2G produced a significantly higher number of indeterminate results in patients with SLE (23/71, 32.4%) compared with those with other CTD (5.7%) or healthy controls (0%) (p < 0.0001 and p < 0.0001). Decreased lymphocyte counts and high SLEDAI scores in SLE patients were shown to be risk factors for indeterminate results by multivariate analysis (p = 0.02 and p = 0.04). Among all patients with CTD, SLE itself and lymphocytopenia were found to be independent risks for indeterminate results (p = 0.00000625 and p = 0.000107). In conclusion, QFT-2G may have more potential to assist in the diagnosis of active and latent MTB infection than TST in SLE patients. However, because of the high frequency of indeterminate results, caution must be used when interpreting the results of QFT-2G among SLE patients, especially those who have parallel or subsequent flares.