The mycobacterium tuberculosis (TB) IFN-γ release assay (TB-IGRA) assesses peripheral blood cell release of IFN-γ upon ex vivo exposure to mitogen (IGRA-MT), TB antigen or a negative/nil control (IGRA-NL); IGRA-NL is a measure of spontaneous IFN-γ release (SIR). Here, we investigate the diagnostic associations of elevated SIR and the potential use of IGRA-NL as a novel biomarker in SLE.We analysed diagnostic code frequencies among 11 823 individuals undergoing TB-IGRA testing between 2010 and 2015 in a large urban US health-care system. To study the relationship between IGRA-NL and SLE, we identified 99 individuals with SLE and TB-IGRA test results then assessed correlations between IGRA-NL, normalized IGRA-NL (the quotient of IGRA-NL/IGRA-MT), disease manifestations and disease activity.We identified a discovery cohort of 108 individuals with elevated SIR (>5 s.d. above median) that was significantly enriched for a limited set of diagnoses, including SLE, TB infection, haemophagocytic lymphohistiocytosis and HIV infection. In SLE patients undergoing TB-IGRA testing, normalized IGRA-NL correlated better with disease activity than did anti-dsDNA or complement levels. This relationship appeared to reflect interactions between normalized IGRA-NL and the presence of acute skin disease, hypocomplementemia, fever and thrombocytopenia.Elevated SIR appears to be associated with a limited number of disease processes, including SLE. The diagnostic utility of SIR remains to be determined. IFN-γ activation, as measured by the TB-IGRA test, may offer a readily available tool for assessing disease activity in patients with SLE.