BACKGROUND: Evidence from animal models and observational epidemiology points to a role for chronic inflammation, in which interleukin 6 (IL-6) is a key player, in the pathophysiology of type 2 diabetes (T2D). However, it is unknown whether IL-6 mediated inflammation is implicated in the pathophysiology of T2D. METHODS: We performed a meta-analysis of 15 prospective studies to investigate associations between IL-6 levels and incident T2D including 5,421 cases and 31,562 non-cases. We also estimated the association of a loss-of-function missense variant (Asp358Ala) in the IL-6 receptor gene (IL6R), previously shown to mimic the effects of IL-6R inhibition, in a large trans-ethnic meta-analysis of six T2D case-control studies including 260,614 cases and 1,350,640 controls. FINDINGS: In a meta-analysis of 15 prospective studies, higher levels of IL-6 (per log pg/mL) were significantly associated with a higher risk of incident T2D (1·24 95% CI, 1·17, 1·32; P = 1 × 10-12). In a trans-ethnic meta-analysis of 260,614 cases and 1,350,640 controls, the IL6R Asp358Ala missense variant was associated with lower odds of T2D (OR, 0·98; 95% CI, 0·97, 0·99; P = 2 × 10-7). This association was not due to diagnostic misclassification and was consistent across ethnic groups. IL-6 levels mediated up to 5% of the association between higher body mass index and T2D. INTERPRETATION: Large-scale human prospective and genetic data provide evidence that IL-6 mediated inflammation is implicated in the etiology of T2D but suggest that the impact of this pathway on disease risk in the general population is likely to be small. FUNDING: The EPICNorfolk study has received funding from the Medical Research Council (MRC) (MR/N003284/1, MC-UU_12015/1 and MC_PC_13048) and Cancer Research UK (C864/A14136). The Fenland Study is funded by the MRC (MC_UU_12015/1 and MC_PC_13046).