Cytoplasmic STAT3 was inversely associated with the density of CD3<sup>+</sup> (<i>P</i> = 0.012), CD8<sup>+</sup> (<i>P</i> = 0.003), and FOXP3<sup>+</sup> T lymphocytes (<i>P</i> = 0.002) within the cancer cell nests and was associated with an elevated systemic inflammatory response as measured by modified Glasgow Prognostic Score (mGPS2: 19% vs. 4%, <i>P</i> = 0.004).The combination of nuclear STAT3/pSTAT3 stratified 5-year survival from 81% to 62% (<i>P</i> = 0.012), however, was not associated with survival independent of venous invasion, tumor perforation, or tumor budding.<b>Conclusions:</b> In patients undergoing colorectal cancer resection, STAT3 expression was associated with adverse host inflammatory responses and reduced survival.