Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease with clinical sequelae such as itching, dyspigmentation, and scarring.We applied a previously described modular analysis approach to assess the molecular heterogeneity of CLE patients.Whole blood transcriptomes of RNA sequencing data from a racially and ethnically diverse group of CLE patients (n=62) were used to calculate gene co-expression module scores. An unsupervised cluster analysis and K-means clustering based on these module scores were then performed. We used Fisher's exact tests and Kruskal Wallis tests to compare characteristics between patient clusters.Six unique clusters of CLE patients were identified from the cluster analysis. We observed that seven inflammation modules were elevated in two CLE patient clusters. Additionally, these clusters were characterized by interferon, neutrophil and cell death signatures, suggesting that interferon-related proteins, neutrophils, and cell death processes could be driving the inflammatory response in these subgroups. Three different clusters had a predominant T cell signature, which were supported by lymphocyte counts.Our data support a diverse molecular profile in CLE that further adds to the clinical variations of this skin disease, and may affect disease course and treatment selection. Future studies with a larger and diverse CLE patient cohort are warranted to confirm these findings.