Increased serum concentrations of FFA, bilirubin, and carboxyl-methyl-propyl-furanpropionic acid, accumulating in chronic renal failure in direct relationship with serum creatinine, have all been implicated in the pathogenesis of the low T3 syndrome during illness. Cytokines may also be involved in the sick euthyroid syndrome. In contrast to interleukin-1 (IL-1) and tumor necrosis factor-alpha, IL-6 is usually detectable in serum during illness and acts as a systemic hormone. We studied the association between serum T3 and IL-6 in consecutive hospital admissions with a wide variety of medical conditions. Patients were divided into group A (T3, > or = 1.30 nmol/L; T4, > or = 75 nmol/L; n = 41), group B (T3, < 1.30 nmol/L; T4, > or = 75 nmol/L; n = 46), and group C (T3, < 1.30 nmol/L; T4, < 75 nmol/L; n = 13). Serum IL-6 levels in groups C and B were higher than those in group A (median values 59, 39, and 9 U/mL, respectively; P < 0.01). Serum creatinine and bilirubin/albumin ratios were similar in the three groups, but the FFA/albumin ratio in group C was higher than in group A (P < 0.05). When all patients were analyzed together, serum T3 was negatively correlated to serum IL-6 (r = -0.56; P < 0.001), bilirubin/albumin ratio (r = -0.29; P = 0.004), and FFA/albumin ratio (r = -0.21; P = 0.03), but not with creatinine (r = -0.16; P = 0.11). Stepwise multiple regression resulted in the following equation: serum T3 = 2.13-0.18ln(IL-6)-0.15ln(creatinine)-0.094ln(bilirubin /albumin) (r = 0.61). The variability in serum T3 was accounted for 28% by ln(IL-6), 5% by ln(creatinine), and 4% by ln(bilirubin/albumin). FFA/albumin did not contribute in this respect. We conclude that the low T3 syndrome in nonthyroidial illness is associated with high serum IL-6 levels. However, even when IL-6 is assumed to play a causative role, the variation of serum T3 in NTI-patients remains largely unexplained.