Elevated interleukin-6 (IL-6) levels are associated with type 2 diabetes, but its role in glucose metabolism is controversial. We investigated the effect of IL-6 on insulin-stimulated glucose metabolism in type 2 diabetes patients, and hypothesized that an acute, moderate IL-6 elevation would increase the insulin-mediated glucose uptake. Men with type 2 diabetes not treated with insulin (n=9, age [mean±SD] 54.9±9.7 years, BMI 34.8±6.1 kg/m², HbA1c % 7.0±1.0) received continuous intravenous infusion with either recombinant human IL-6 (rhIL-6) or placebo. After one hour with placebo or rhIL-6, a 3-hour hyperinsulinemic-isoglycemic clamp was initiated. Whole body glucose metabolism was measured using stable isotope labeled tracers. Signal transducer and activator of transcription 3 (STAT3) phosphorylation and suppressor of cytokine signaling 3 (SOCS3) expression were measured in muscle biopsies. Whole body energy expenditure was measured using indirect calorimetry. In response to the infusion of rhIL-6, circulating levels of IL-6 (P<0.001), neutrophils (P<0.001), and cortisol (P<0.001) increased, while lymphocytes decreased (P<0.01). However, IL-6 infusion did not change glucose infusion rate, rate of appearance, or rate of disappearance during the clamp. While IL-6 enhanced phosphorylation of STAT3 in skeletal muscle (P=0.041), the expression of SOCS3 remained unchanged. Whole body oxygen uptake (P<0.01) and expired carbon dioxide (P<0.01) increased during rhIL-6 infusion. In summary, although IL-6 induced local and systemic responses, the insulin-stimulated glucose uptake was not affected. While different contributing factors may be involved, our results are in contrast to our hypothesis as well as previous findings in young, healthy men.