To assess the genetic influence on cytokine production and its contribution to fatal outcome, we determined the capacity to produce tumour necrosis factor-α (TNFα) and interleukin-10 (IL-10) in families of patients who had had meningococcal disease. We studied 190 first-degree relatives of 61 patients with meningococcal disease; we also studied 26 monozygotic twins. Production of cytokines was determined during endotoxin stimulation of whole-blood samples ex-vivo. Heritability was estimated in a pedigreebased maximum-likelihood model. DNA was typed for the G to A transition polymorphisms at position −308 and −238 in the TNF gene promoter. Heritability in monozygotic twins was 0·60 for the production of TNF and 0·75 for the production of IL-10. Families with low TNF production had a tenfold increased risk for fatal outcome (OR 8·9, 95% CI 1·8–45), whereas high IL-10 production increased the risk 20-fold (19·5, 2·3–165). Families with both characteristics had the greatest risk. The transition polymorphisms in the TNF gene promoter were not associated with outcome. Genetic factors substantially influence production of cytokines. An innate anti-inflammatory cytokine profile may contribute to fatal meningococcal disease.