A complete understanding of disease is not possible without being conceptually grounded by etiology. Many findings are consistent with the possibility that Epstein-Barr virus (EBV) is an etiology for Systemic Lupus Erythematosus (SLE), but none that establish EBV as an original cause of SLE. We propose to extend our continuing work using sera collected over time from active duty military, available through the Department of Defense Serum Repository (DoDSR), and apply a Matched Etiologic Exposure Window (MEEW) strategy to test whether EBV is, indeed, an etiology of SLE. The exposure window is defined from the moment that the first serum is collected to the time that the serum is collected containing the earliest SLE-specific evidence of an SLE pathologic process. During the exposure window, under the expectation that pre-disease cases and matched controls are indistinguishable, variables that do not affect SLE etiology will follow the null expectation of equivalence in the Cases and Matched-Controls. We will test whether EBV infection and anti-EBNA1 antibodies deviate from the expected null distribution. If the associations are obtained and cannot be alternatively explained, by error, reverse causation, confounding, or pleiotropy, then we conclude that the exposure showing association is probably a causal etiology. This approach has been recently used to establish that EBV is a cause of Multiple Sclerosis (MS) with Hazard Ratio (HR)=32, p<0.0001, in the absence of any evident alternative explanation. We have had much experience working with sera and data from the DoDSR, publishing 11 DoDSR papers describing the sequence of events that occur before the SLE is apparent. This experience allows us to make reliable estimates of the needed sample size and establishes technical competence with the needed assays and analyses. To obtain an adequate sample size we will include Veterans seeking healthcare in the US Department of Veterans Affairs (VA) who had their first diagnosis of SLE in the VA soon after DoD service separation. We will test the hypothesis that EBV causes SLE using the MEEW approach. We will ascertain alleged SLE cases, identify those satisfying SLE classification criteria, and test their first DoDSR serum samples for the EBV infection and anti-EBNA1 antibodies. Our published data are consistent with anti-EBNA1 antibodies being the primordial precursor from which SLE-specific autoantibodies develop via molecular mimicry mechanisms. Experiment 1 will test whether EBV-infected and anti-EBNA1 negative (EBV+/aEBNA1−) Cases develop anti- EBNA1 more frequently in the exposure window than do Matched-Controls who are also EBV+/aEBNA1− and matched on age, ancestry, sex, time of service, serum samples available, and, for VA-ascertained SLE cases, time of first seeking VA care. The relationship of the appearance of anti-EBNA1 in relation to the appearance of SLE-specific antibodies will define the exposure using conditional logistic regression for ...