Serum samples from 55 patients with systemic lupus erythematosus (SLE) were selected for the absence of anti-extractable nuclear antigen antibodies after routine immunodiffusion tests. These sera were immunoblotted for anti-Sm and anti-RNP antibodies on a HeLa cell nuclear extract. Ten (18%) were negative and 45 (82%) produced complex patterns: 10 (18%) suggestive of anti-Sm, three (5%) anti-RNP, and 32 (58%) a combination of anti-Sm and anti-RNP antibodies. These data were very similar to those obtained from sera from a control group of 28 SLE sera selected for positivity of anti-Sm and anti-RNP precipitins with the immunodiffusion test. IgM isotype antibodies to the D peptide were significantly more prevalent than IgG isotype antibodies, whereas antibodies to the 68 kD polypeptide were of both IgM and IgG isotypes. Sera with an anti-Sm/RNP immunoblotting pattern stemmed from a group of patients with SLE with a higher titre of anti-dsDNA antibodies. Among clinical symptoms, the incidence of haemolytic anaemia was higher in the group of patients with the anti-Sm immunoblotting profile. Patients with an anti-RNP immunoblotting profile showed a higher incidence of cutaneous symptoms. It is concluded that immunoblotting for anti-Sm or anti-RNP antibody determination is a very sensitive diagnostic tool in patients with SLE.