Pharmaceutically prepared IgG, pooled from sera of over 2,000 normal individuals, contained both monomeric and dimeric IgG.Each type of IgG bound Iodine-125-labeled interleukin (IL)-1alpha, IL-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. Increased binding to IgG was observed if Iodine-125-IL-1beta was denatured by heating to 39 degrees C. However, the binding of both nondenatured and denatured Iodine-125-IL-1beta was not inhibited by unlabeled IL-1beta. In contrast, binding of Iodine-125-IL-1alpha, Iodine-125-IL-6, and Iodine-125-TNFalpha was inhibited by the corresponding nlabeled cytokine. Papain-digestion of IgG abolished binding of Iodine-125-TNFalpha but failed to influence the displaceable binding of Iodine-125-IL-1alpha and Iodine-125-IL-6. Iodine-125-TNFalpha was a mixture of trimeric and monomeric forms, the latter being the predominant form at lower concentrations. The apparent saturability of Iodine-125-TNFalpha was explained by a higher nonspecific binding of monomeric than of trimeric Iodine-125-TNFalpha to IgG. The amounts of cytokine antibodies in IgG preparations would contribute approximately 2 micrograms anti-IL-1alpha IgG and 1 microgram anti-IL-6 IgG per kg body wt during high dose immune globulin therapy. In conclusion, pharmaceutical preparations of human IgG contain specific and neutralizing, high affinity antibodies against IL-1alpha and IL-6, but not against TNFalpha or IL-1beta. There are significant methodological pitfalls that hamper detection of IgG autoantibodies against cytokines. (J. Clin. Invest. 1993. 92:2533-2539.) Key words: human immune globulin, IgG. autoantibodies to cytokines. interleukin-1alpha. interleukin-6.