Responses of the IgE type to various nuclear antigens have been explored using the human basophil degranulation test (HBDT) to single (SS) and double-stranded (DS) deoxyribonucleic acid (DNA), nuclear ribonucleoprotein (nRNP), and Sm antigens. This study was conducted on systemic lupus erythematosus (SLE) patients as compared to rheumatoid arthritis (RA) polymyositis (PM), scleroderma (SCL) and mixed connective tissue disease (MCTD). SLE and MCTD patients showed a high level of basophil degranulation to the four antigens. Degranulation to nRNP protein was higher in MCTD than in SLE cases. HBDT to the four antigens were constantly negative in control donors and in RA, PM and SCL. Basophil degranulation to DS-DNA in SLE was blocked by previous exposure of the blood to anti-human-IgE antiserum. These results exemplify the specificity of the HBDT, making this simple and fast test a useful tool in the diagnosis of connective tissue diseases.