Nucleolin, also known as C23, is an abundant nucleolar phosphoprotein implicated in the synthesis, processing, and transport of ribosomal RNA and gene transcription. It mainly localizes to the dense fibrillar regions of the nucleolus. The association of several structural domains allows the interaction of nucleolin with DNA and RNA sequences and nucleic acid-binding proteins such as histone H1. More precisely, nucleolin has been implicated in chromatin structure, rDNA transcription, rRNA maturation, ribosome assembly, and nucleocytoplasmic transport. The development of distinct combinations of autoantibodies has been recognized as an important characteristic of certain systemic autoimmune diseases. Nucleolin has been identified as autoantigen in patients with systemic connective tissue diseases (SCTD) including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). A strong association of IgM autoantibodies to nucleolin and histone H1 in the serum of patients with SLE could be shown.