PURPOSE: Various lines of evidence suggest that proinflammatory factors may play a role in tumor growth and metastasis, the leading cause of cancer-related mortality. However, most evidence originates from animal models, only few human studies reported an association between proinflammatory cytokines and death from cancer. Here, we investigated the association between circulating levels and innate production capacity of proinflammatory cytokines and cancer incidence and mortality in the PROspective Study on Pravastatin in the Elderly at Risk (PROSPER). EXPERIMENTAL DESIGN: Circulating levels of interleukin 6 (IL-6) and C-reactive protein were measured in all 5,804 participants of the PROSPER study. The innate production capacity of IL-6, IL-1beta, and tumor necrosis factor alpha (TNF-alpha) were measured in a random sample of 403 subjects. RESULTS: We showed that high circulating inflammatory markers were associated with an increased risk for cancer incidence and death from cancer during follow-up (all P < 0.05). Moreover, high innate proinflammatory cytokine production capacity is associated with an increased risk for death from cancer (all P < 0.04) but not with higher cancer incidence during follow-up (all P > 0.6). CONCLUSIONS: High innate production capacity of proinflammatory cytokines is associated with an increased risk for death from cancer, probably because of increased tumor growth and metastasis. Because there was no association between innate production capacity and cancer incidence, the association between circulating levels and cancer incidence at least partially reflects reversed causality. (Clin Cancer Res 2009;15(24):7744-8).