Because low tumor necrosis factor-α (TNF-α) production has been reported in malnourished children, in contrast with high production of TNF-α in experimental protein-energy malnutrition, we reevaluated the production of TNF-α in whole blood cultures from children with primary malnutrition free from infection, and in healthy sex- and age- matched controls. Mononuclear cells in blood diluted 1:5 in endo- toxin-free medium released TNF-α for 24 h. Spontaneously released TNF-α levels (mean ± SEM), as measured by enzyme immunoassay in the supernatants of unstimulated 24-h cultures, were 10,941 ± 2,591 pg/ml in children with malnutrition (N = 11) and 533 ± 267 pg/ml in controls (N = 18) (P < 0.0001). TNF-α production was increased by stimulation with lipopolysaccharide (LPS), with maximal production of 67,341 ± 16,580 pg/ml TNF-α in malnourished children and 25,198 ± 2,493 pg/ml in controls (P = 0.002). In control subjects, LPS dose- dependently induced TNF-α production, with maximal responses obtained at 2000 ng/ml. In contrast, malnourished patients produced significantly more TNF-α with 0.02-200 ng/ml LPS, responded maxi- mally at a 10-fold lower LPS concentration (200 ng/ml), and presented high-dose inhibition at 2000 ng/ml. TNF-α production a) was signifi- cantly influenced by LPS concentration in control subjects, but not in malnourished children, who responded strongly to very low LPS concentrations, and b) presented a significant, negative correlation (r = -0.703, P = 0.023) between spontaneous release and the LPS concentration that elicited maximal responses in malnourished pa- tients. These findings indicate that malnourished children are not deficient in TNF-α production, and suggest that their cells are primed for increased TNF-α production.