Monocytes and macrophages are major components of the tumor microenvironment, but their contributions to human cancer are poorly understood. We used molecular profiling combined with functional assays to investigate the role of these cells in human renal cell carcinoma (RCC). Blood monocytes from RCC patients displayed a tumor-promoting transcriptional profile that supported functions like angiogenesis and invasion. Induction of this protumor phenotype required an interleukin-1 receptor (IL-1R)-dependent mechanism. Indeed, targeting of IL-1-IL-1R axis in a human RCC xenograft model abrogated the protumor phenotype of tumor-associated macrophages (TAMs) and reduced tumor growth in vivo. Supporting this, meta-analysis of gene expression from human RCC tumors showed IL1B expression to correlate with myelomonocytic markers, protumor genes, and tumor staging. Analyzing RCC patient tumors confirmed the protumor phenotype of TAMs. These data provide direct evidence for a tumor-promoting role of monocytes and macrophages in human cancer and indicate IL-1-IL-1R as a possible therapeutic target. •Monocytes and macrophages show a protumor phenotype in a human cancer setting•The protumor phenotype is regulated by an IL-1 receptor-dependent mechanism•Targeting this mechanism abrogated macrophage protumor phenotype and tumor in vivo Monocytes and macrophages are major components of the tumor microenvironment, but their contributions to human cancer are poorly understood. Biswas and colleagues provide transcriptional, functional, and mechanistic data demonstrating a tumor-promoting phenotype of these cells in a human cancer setting.