Anti-ribosomal P protein antibodies (anti-rib-P Abs) recognize three specific ribosomal proteins (P0, P1 and P2) located in the large ribosome's subunit. These autoantibodies (autoAbs) are restricted to systemic lupus erythematosus (SLE) during active disease and associated with neuropsychiatric, renal and hepatic involvement. A preferential association of anti-rib-P with anti-Sm and/or anti-DNA Abs is, possibly due, at least in part, to cross-reactivity. The prevalence of anti-rib-P Abs is influenced by ethnic variations and most common in Asians. The P proteins are immunogenic in several ways. They represent, indeed, an antigenic target not only for autoAbs in SLE but also for immune responses against some parasitic infection, including Trypanosoma cruzi, the protozoa inducing Chagas disease, Leishmania and the allergic response to Aspergillus fumigatus, Alternaria alternata and Cladosporium herbarum. Anti-rib-P Abs is more frequently found in sera containing peculiar Ab specificities. A first observation pointed to a higher frequency of anti-rib-P Abs in anti-Sm Ab positive sera. The possible association of anti-rib-P Abs with anti-phospholipid Abs was investigated by some, but requires further clinical and experimental studies to confirm it and to test possible cross-reactions between such families of autoAbs.