Neutrophils are emerging as important mediators in cancer progression. Recent studies associated neutrophils with poor clinical outcome of HNC patients and showed that HNC induces recruitment, survival, and release of proinflammatory factors by neutrophils in vitro. The molecular mechanisms through which HNC and other cancers modulate neutrophil biology are currently unknown. To explore these mechanisms, we used an in vitro system that models the interaction between human HNC cells and neutrophils or neutrophilic-differentiated HL-60 cells, respectively. We show that HNC-derived factors activate p38-MAPK in neutrophils, which partly promotes neutrophil survival, but not neutrophil recruitment and motility. Most importantly, HNC-induced p38-MAPK activation strongly stimulates the release of CCL4, CXCL8, and MMP9 by neutrophils. We identify CREB and interestingly, p27 phosphorylated at T198 as downstream members of the HNC-induced p38-MAPK signaling cascade. Using siRNA technology, we demonstrate that p27 and CREB mediate the release of CCL4 and CXCL8 and that CREB, additionally, mediates the release of MMP9. These data unravel novel molecular mechanisms involved in regulation of neutrophil proinflammatory functions. Our studies on human HNC tissues indicate that tumor-infiltrating neutrophils might be a major source of CCL4 and particularly, MMP9 in cancer patients. Thus, our findings provide novel, mechanistic insights relevant for the pathophysiology of HNC and possibly, other types of cancer as well.