Tumor recurrence years after complete surgical resection or complete clinical response to chemotherapy or radiation therapy is one of the major causes of cancer-related deaths. Disseminated tumor cells can lie dormant for extended time before initiating tumor outgrowth. The mechanisms that contribute to reactivation of dormant tumor cells and subsequent cancer recurrence remain mostly unclear. Using p53 induced dormancy models of lung cancer and chemotherapy-induced dormancy model of lung and ovarian cancer, we found a specific mechanism, mediated by stress and neutrophils, that may govern this process. Stress hormones cause rapid release of pro-inflammatory S100A8/A9 proteins by neutrophils. S100A8/A9 induce activation of myeloperoxidase, resulting in accumulation of oxidized lipids in these cells. Upon release from neutrophils these lipids upregulate the fibroblast growth factor pathway in tumor cells, causing tumor cell exit from the dormancy and formation of new tumor lesions. Higher serum concentrations of S100A8/A9 were associated with shorter time to recurrence in patients with non-small cell lung cancer after complete tumor resection. Targeting of S100A8/A9 or β2 adrenergic receptors abrogated stress-induced reactivation of dormant tumor cells in mice. These observations demonstrate a mechanism linking stress and specific neutrophil activation with early recurrence in cancer.