Background: In patients with colorectal cancer (CRC), the local and systemic inflammatory responses (LIR and SIR) are important determinants of disease progression, and may be linked by activation of the IL-6/JAK/STAT3 pathway. The present study examines the associations between STAT3 expression and activation with LIR and SIR of patients undergoing resection of CRC. Methods: Patients with stage I-III CRC who underwent curative resection in a single institution and who were included in a previously constructed tissue microarray were studied. IHC was utilised to examine cytoplasmic total STAT3 and nuclear phosphorylated STAT3_Tyr705 (pSTAT3) expression. The relationship between STAT3/pSTAT3 expression and clinicopathological characteristics, LIR (Klintrup-Makinen (KM) grade, CD3⁺ and CD8⁺T-cell density) and SIR (modified Glasgow Prognostic Score (mGPS)) and cancer-specific survival (CSS) was examined. Results: 201 patients were included. Cytoplasmic STAT3 expression was associated with nuclear pSTAT3 expression (P= 0.019). Increased cytoplasmic STAT3 expression was associated with high density of T-cells within the intraepithelial compartment (CD3⁺: low STAT3 – 49% vs. high STAT3 – 29%, P= 0.008; CD8⁺: low STAT3 – 43% vs. high STAT3 – 20%, P = 0.002) and with an elevated mGPS (mGPS > 1: low STAT3 – 31% vs. high STAT3 – 49%, P= 0.003) but not with any other clinicopathological features. Increased nuclear pSTAT3 expression was associated with younger age and lymph node involvement (P< 0.05) but was not associated with the LIR or SIR. Combined assessment of cytoplasmic STAT3 and nuclear pSTAT3 expression stratified 5-year CSS from 78% (both low) to 50% (both high) (P= 0.006). Conclusions: Activation of the IL-6/JAK/STAT3 pathway may be an important determinant of the LIR and SIR in patients with colorectal cancer. Furthermore, assessment of host inflammatory responses may identify patients likely to benefit from therapies targeting this pathway. Taken together with the results of recent clinical trials, the results of the present study suggest that recruitment of patients into future trials of such agents should be stratified by the inflammatory status of the patient.