Calcium transport by the cardiac sarcoplasmic reticulum is depressed in human dilated cardiomyopathy, but the mechanisms involved are not clear. The possible involvement of immunological mechanisms was explored by evaluating the effect of sera from 49 patients with dilated cardiomyopathy on oxalate-facilitated Ca2+ uptake. In 14 of these patients, serum or IgG induced a time- and concentration-dependent decline (29 +/- 4% at 100-fold serum dilution) in Ca2+ transport. In 14 patients, autoantibodies against the beta 1-adrenoceptor were also demonstrated by a ligand binding inhibition assay. Serum from these patients inhibited the isoproterenol-mediated stimulation of Ca2+ uptake in permeabilized cardiac myocytes, but did not prevent the effect of protein kinase A. Anti-beta-receptor antibodies were present in 50% of the sera inhibiting Ca2+ uptake compared to 20% of those without inhibitory activity, (p less than 0.01). There was a strong correlation between the inhibition of sarcoplasmic reticulum Ca2+ transport and the HLA-DR4 phenotype (78% compared to 30% in patients with no inhibitory effect). These results suggest that immunological mechanisms play an important role in modifying sarcoplasmic reticulum function in about a third of the patients with detailed cardiomyopathy.