Systemic lupus erythematosus (SLE) is characterized by abnormalities in the function of T and B lymphocytes and in the signaling pathways induced through their receptors. Cbl-b is an intracellular adaptor protein that plays a key role in the negative regulation of lymphocyte activity. We explored the expression and function of Cbl-b in T lymphocytes from SLE patients. In addition, the possible association of SLE and a single nucleotide polymorphism (SNP) of the Cblb gene was determined. We studied 150 SLE patients, 163 healthy individuals, and 14 patients with rheumatoid arthritis (RA). The expression of Cbl-b was analyzed in the peripheral blood mononuclear cells, and the negative regulatory function of Cbl-b was assessed by analyzing actin polymerization and the phosphorylation of JNK and c-Jun induced through CD3. Furthermore, the 2126(A/G) SNP of the Cblb gene was detected by real-time polymerase chain reaction. We found a significant small reduction in the expression of Cbl-b as well as increased levels of activation of c-Jun and actin polymerization in T lymphocytes from patients with SLE compared with healthy controls or RA patients. In addition, a significant association between the 2126(A/G) SNP and SLE was detected. Our data suggest that Cbl-b may contribute to the deregulated activation of T lymphocytes observed in SLE.