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Objectives: Tumor‐infiltrating lymphocytes (TIL), particularly CD8+ TILs in patients with colorectal cancer (CRC), are highly prognostic in the early‐disease stages (I‐II). In metastatic disease (stage IV; mCRC), their influence is less well defined. It has presumably failed to contain tumor cells to the primary site; however, is this evident? We explored the prognostic impact of TILs at the primary site in patients who presented de novo with mCRC. Methods: Treatment‐naïve patients (109) with mCRC were assessed for CD8+ TILs and PD‐L1 expression. Microsatellite instability (MSI) was evaluated by IHC for PMS2 and MSH6 proteins and/or by PCR using the Bethesda panel. Results: Microsatellite instability‐high tumors had significantly more CD8+ TILs, with no significant survival advantage observed between MSI‐H and microsatellite stable (MSS) tumors (12 vs 19 months, P = 0.304). TIL density for all cases had no impact on OS (low: 20 vs high: 13 months, P = 0.426), while PD‐L1 of 1% or higher was associated with reduced mean survival (9.6 vs 18.9 months; P = 0.038). MSI‐H tumors and associated immune cells had higher PD‐L1 expression than in MSS cases. A positive correlation between PD‐L1 on immune cells and CD8+ve TILs was found. A subset of MSS tumors had relatively high TILs approximating that of MSI‐H tumors. Conclusion: In contrast to early‐stage CRC, the immune response in primary tumors of patients with de novo mCRC does not appear to influence survival. A subgroup of MSS tumors was identified with increased TILs/PD‐L1 comparable to MSI‐H tumors, traditionally not be considered for immune checkpoint blockade and perhaps should be. [ABSTRACT FROM AUTHOR]