Abstract Purpose: An efficient adaptive immunity is critical for a longer survival in cancer. We investigated the prognostic value of tumor infiltration by CD8+ T cells expressing the chemokine-receptor-7 (Tccr7) and the correlation between tumor infiltration by Tccr7 and regulatory CD4+FoxP3+ T cells (Treg) in 76 metastatic colorectal cancer (mCRC) patients enrolled in a phase III trial. Experimental Design: Tccr7 and Treg cell infiltration in tumor samples was quantified by immunohistochemistry. The correlation among Tccr7, Treg tumor infiltration, and patients' outcome was evaluated. Results: High Tccr7 tumor infiltration was predictive of prolonged OS [high vs. low Tccr7 score: median 38 months (95% CI: 24.5–51.4) vs. 20 months (95% CI: 11.4–28.5); HR = 0.48 (95% CI: 0.24–0.96); P = 0.03] and prolonged progression-free survival [PFS; high vs. low Tccr7 score: median 12 months (95% CI: 7.7–16.2) vs. 7 months (95% CI: 5.2–8.7); HR = 0.54 (95% CI: 0.28–1.01); P = 0.01] after front-line chemotherapy. Regression analysis did not show correlation between Tccr7 and Treg infiltration levels. However, the cluster of patients showing concomitant high infiltration by both Tccr7 and Treg disclosed a favorable outcome [double high vs. double low tumor infiltration score: median OS = 35 months (95% CI: 20.8–49.1) vs. 17 months (95% CI: 4.6–29.3); HR = 0.32 (95% CI: 0.12–0.87); P = 0.02 and median PFS = 11 months (95% CI: 9.4–12.5) vs. 5 months (95% CI: 2.2–7.7); HR = 0.43 (95% CI: 0.17–1.06); P = 0.01]. Conclusions: High Tccr7 tumor infiltration score is a favorable prognostic factor for mCRC. Our findings underline the relevance of microenvironment-related immunologic events for patient outcome. Clin Cancer Res; 18(3); 850–7. ©2011 AACR.