Objective Explore the hypothesis that cases of SLE will be found more frequently in community members with high prior uranium exposure in the Fernald Community Cohort (FCC). Methods A nested case control study was performed. The FCC is a volunteer population that lived near a uranium ore processing plant in Fernald, Ohio, USA during plant operation and members were monitored for 18 years. Uranium plant workers were excluded. SLE cases were identified using American College of Rheumatology classification criteria, laboratory testing, and medical record review. Each case was matched to four age-, race-, and sex-matched controls. Sera from potential cases and controls were screened for autoantibodies. Cumulative uranium particulate exposure was calculated using a dosimetry model. Logistic regression with covariates was used to calculate odds ratios (OR) with 95% confidence intervals (CI). Results The FCC includes 4,187 individuals with background uranium exposure, 1,273 with moderate exposure, and 2,756 with higher exposure. SLE was confirmed in 23 of 31 individuals with a lupus ICD9 code, and in 2 of 43 other individuals prescribed hydroxychloroquine. The female:male ratio was 5.25:1. Of the 25 SLE cases, 12 were in the higher exposure group. SLE was associated with higher uranium exposure (OR 3.92, 95% CI 1.131-13.588, p = 0.031). Conclusion High uranium exposure is associated with SLE relative to matched controls in this sample of uranium exposed individuals. Potential explanations for this relationship include possible autoimmune or estrogen effects of uranium, somatic mutation, epigenetic effects, or effects of some other unidentified accompanying exposure.