Antibodies to the ribosomal P proteins (anti-P) were detected, by Western blot analysis, in the sera of 20 of 114 patients with various autoimmune disorders. Eighty-five percent of the patients with anti-P had systemic lupus erythematosus (SLE). Of 93 randomly selected patients, the frequency of anti-P was 7 of 59 SLE patients (12%) and 0 of 34 non-SLE patients. Approximately one-third of the patients with anti-P antibodies were male; approximately half were black. In contrast to the findings of some previous studies which used isolated ribosomes as antigen, an increased frequency of renal disease was not observed. Although the overall frequency of central nervous system lupus was similar in SLE patients with and those without anti-P, 6 of 6 patients with psychosis had anti-P antibodies. Western blotting was the most sensitive and specific method for the detection of anti-P antibodies; counter-immunoelectrophoresis and cytoplasmic indirect immunofluorescence were positive in only 47% and 65% of the anti-P-positive patients, respectively. Although 53% of the SLE patients with anti-P had concomitant anti-Ro antibodies, none had anti-La (as detected by counterimmunoelectrophoresis). Anti-P antibodies, therefore, appear to be relatively specific serologic markers for SLE and may be detected in the serum even when antibodies to double-stranded DNA are not found.