Dysregulation of Ras guanyl nucleotide-releasing protein 1 (RasGRP1) in mice results in a systemic lupus erythematosus (SLE)-like disorder. We therefore looked for defective isoforms and/or diminished levels of human RasGRP1 in a cohort of SLE patients. PBMCs were collected from twenty healthy individuals and thirty-two patients with SLE. mRNA was isolated and five RasGRP1 cDNAs from each subject were sequenced. T cell lysates from healthy controls and SLE patients also were evaluated for their levels of RasGRP1 protein. The accumulated data led to the identification of 13 new splice variants of the human RasGRP1 gene. Not only did our SLE patients have increased levels and types of these defective transcripts relative to normal individuals, two SLE patients were identified whose PBMCs and T cells contained very little, if any, functional RasGRP1 mRNA and protein. The presence of aberrantly spliced RasGRP1 transcripts also was correlated with lower levels of RasGRP1 protein in the patients' T cells. The lack of the normal isoform of RasGRP1 in some SLE patients and the increased prevalence of defective isoforms of RasGRP1 in others raise the possibility that dysregulation of this signaling protein contributes to the development of autoimmunity in a subset of SLE patients.