Purpose: The major pathologic markers of prognosis in colorectal cancer include vascular invasion by tumor cells, invasion of adjacent lymph nodes, and perforation of the serosal wall. Recent work suggests that a high density of tumor-infiltrating lymphocytes (TIL) is associated with good outcome independently of these established prognostic markers. The aim of the present study was to investigate the prognostic significance of TILs and other routinely reported pathologic features in colon cancer, particularly in relation to the use of adjuvant chemotherapy.Experimental Design: Pathologic markers, disease-specific survival, and the use of adjuvant chemotherapy were recorded in a retrospective, population-based series of 1,156 stage III colon cancer patients with a median follow-up time of 52 months.Results: In patients treated by surgery alone (n = 851), markers with significant prognostic value included poor histologic grade,T4 stage, N2 nodal status, vascular invasion, and perforation, but not the presence of TILs. In patients treated with 5-fluorouracil-based chemotherapy (n = 305), TILs were associated with significantly improved survival [hazard ratio (HR), 0.52; 95% confidence interval, 0.30-0.91; P = 0.02] and perforation with a trend for improved survival (HR, 0.67; 95% confidence interval, 0.27-1.05;P = 0.16). Patients with TILs or perforation seemed to gain more survival benefit from chemotherapy (HR, 0.22 and 0.21, respectively) than patients without these features (HR, 0.84 and 0.82, respectively).Conclusion: The apparent survival advantage from 5-fluorouracil associated with TILs and perforation requires confirmation in prospective studies. Because the presence of TILs reflects an adaptive immune response and perforation is associated with inflammatory response, these results suggest that there may be interactions between the immune system and chemotherapy leading to improved survival of colon cancer patients.