Epidemiologic studies have shown an inverse association between atopy and malignant lymphoma, but results are inconsistent. We investigated levels of IgE, before and after commencement of treatment, and evaluated lymphoma risk in relation to total and specific IgE levels. Serum levels of IgM, IgA, and IgG were also measured. We enrolled 467 newly diagnosed lymphoma cases and 544 hospital controls, matched for age, sex, and hospital. Lymphomas were histologically confirmed and categorized according to the WHO classification. Subjects provided blood for analysis of total and specific IgE levels, and total IgM, IgA, and IgG levels. Additional information was collected by interviewer-administered questionnaire. Controlling for age, sex, center, smoking status, and any treated asthma or eczema, we found that the overall risk of lymphoma was significantly lower in the high [odds ratio (OR), 0.39; 95% confidence interval (95% CI), 0.28-0.54] and middle (OR, 0.55; 95% CI, 0.40-0.74) tertiles for total serum IgE compared with the low tertile. Specific IgE to common aeroallergens (defined as >or=0.35 kU/L) was also inversely associated with risk of lymphoma (OR, 0.67; 95% CI, 0.45-1.00). Lymphoma was associated with IgA and IgM but not IgG. Mean levels of all immunoglobulins were decreased with more advanced malignancy, and total serum IgE levels were lower before treatment. The data suggest that the low levels of immunoglobulins seen in a wide range of lymphoma cases is likely to be linked to a lymphogenesis process rather than resulting from a selective protection due to an atopic process. Long-term cohort studies may be fundamental to fully evaluate these associations.