Abstract Background Histological lymphocytic reaction is regarded as an independent prognostic marker in colorectal cancer. Considering the lack of adequate statistical power, adjustment for selection bias and comprehensive tumour molecular data in most previous studies, we investigated the strengths of the prognostic associations of lymphocytic reaction in colorectal carcinoma by utilising an integrative database of two prospective cohort studies. Methods We examined Crohn’s-like reaction, intratumoural periglandular reaction, peritumoural reaction and tumour-infiltrating lymphocytes in 1465 colorectal carcinoma cases. Using covariate data of 4420 colorectal cancer cases in total, inverse probability-weighted Cox proportional hazard regression model was used to control for selection bias (due to tissue availability) and potential confounders, including stage, MSI status, LINE-1 methylation, PTGS2 and CTNNB1 expression, KRAS, BRAF and PIK3CA mutations, and tumour neoantigen load. Results Higher levels of each lymphocytic reaction component were associated with better colorectal cancer-specific survival (P_trend < 0.002). Compared with cases with negative/low intratumoural periglandular reaction, multivariable-adjusted HRs were 0.55 (95% CI, 0.42–0.71) in cases with intermediate reaction and 0.20 (95% CI, 0.12–0.35) in cases with high reaction. These relationships were consistent in strata of MSI status or neoantigen loads (P_interaction > 0.2). Conclusions The four lymphocytic reaction components are prognostic biomarkers in colorectal carcinoma.