Abstract p38 MAPK signaling has been implicated in the regulation of processes leading to cancer development and progression. Chronic inflammation is a known risk factor for tumorigenesis, yet the precise mechanism of this association remains largely unknown. The related p38αMAPK (MAPK14) proteins p38γ (MAPK12) and p38δ (MAPK13) were recently shown to modulate the immune response, although their role in tumorigenesis remains controversial and their function in inflammation-associated cancer has not been studied. We analyzed the role of p38γ and p38δ in colon cancer associated to colitis using the azoxymethane/dextran sodium sulphate (AOM/DSS) colitis-associated colon cancer model in wild-type (WT), p38γ-, p38δ-, and p38γ/δ-deficient (p38γ/δ−/−) mice. We found that p38γ/δ deficiency significantly decreased tumor formation, in parallel with a decrease in proinflammatory cytokine and chemokine production. Analysis of leukocyte populations in p38γ/δ−/− mouse colon showed less macrophage and neutrophil recruitment than in WT mice. Furthermore, WT chimeric mice with transplanted p38γ/δ−/− bone marrow had less tumors than WT mice transplanted with WT bone marrow, whereas tumor number was significantly increased in p38γ/δ−/− chimeric mice with WT bone marrow compared with p38γ/δ−/− mice transplanted with p38γ/δ−/− bone marrow. Together, our results establish that p38γ and p38δ are central to colitis-associated colon cancer formation through regulation of hematopoietic cell response to injury, and validate p38γ and p38δ as potential targets for cancer therapy. Cancer Res; 74(21); 6150–60. ©2014 AACR.