Anti-lymphocytic antibodies (anti-LCA) are detected in patients with systemic lupus erythematosus (SLE) with a prevalence ranging from 60–90%. LCA detection is associated with nephritis and neurologic disorders in these patients, and high rates of LCA occur during phases of active SLE. A genetic predisposition is supported by an increased incidence of LCA in SLE consanguineous relatives. LCA are reported in other diseases such as Sjögren syndrome, rheumatoid arthritis, cancer, and infections. The leukocyte common antigen CD45 represents the main target, but the CD45 isoform distribution varies according to the T- or B-cell subset and the lymphocyte activation state, which modifies LCA recognition. Anti-ribosome P0 and anti-β2 microglobulin antibodies have been included in the spectrum of LCA. In vivo, the pathogenic role of LCA on lymphopenia has not been clearly established. Nevertheless, in vitro, LCA may induce apoptosis, complement-dependent lymphocytotoxicity, antibody-dependent cell cytotoxicity, and cell activation with cytokine production, suggesting that LCA may influence lymphocyte functions.