Aim Previously, a distinct class II Luminex-single antigen bead (SAB) pattern was described among patients with systemic lupus erythematous (SLE) and attributed to antibodies targeting denatured antigens. In this study, we identify and describe a novel class I reactivity pattern shared among SLE patients. Methods Routine review of serum samples from transplant patients revealed a recurring pattern of reactivity on class I single antigen bead assays (One Lambda, Inc, lot 10). The pattern included the following beads: HLA-A∗33:03, -A∗36:01, -A∗80:01, -B∗54:01, -B∗53:01, -C∗06:02, -C∗07:02, -C∗18:02, -C∗14:02, -C∗03:03, -C∗03:04, and -C∗15:02. Further investigation was performed to determine the prevalence of this pattern and the specific characteristics of patients in which it occurred. Towards this end, all class I results performed in 2017 on renal transplant candidates/recipients were reviewed retrospectively for the presence of the above pattern. Patient diagnosis and demographic data was obtained from patient laboratory and hospital records. Results In total 5,992 samples from 3,027 patients were reviewed. We observed 105 (1.8%) samples from 58 patients displaying the class I pattern. Twenty-nine percent (n = 17) of these patients had no history of sensitization (e.g. blood transfusion, pregnancy, transplant) and only 29% of samples had distinct antibodies as identified by FlowPRA testing. Of the positive samples, 83% had reactivity against self-antigen involving 1 or more of the alleles in question, with HLA-C∗07:02 being the most common target (45%). Notably, 62% of these patients had a diagnosis of SLE. Conclusions To our knowledge, this is the first description of a distinct class I Luminex-SAB pattern with a prevalence in patients with SLE. This pattern was found in patients with no sensitization history, negative FlowPRA, and/or antibody to self-antigen(s). Epitope analysis failed to reveal a common determinant(s) to explain this pattern of reactivity. Given these findings, this pattern likely represents antibody targeting denatured antigen/unique peptide, molecular mimicry, autoimmunity, or a combination of some/all these factors.