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BACKGROUND: Blood vessel invasion has been associated with poor outcome in colorectal cancer (CRC), whereas the prognostic impact of lymphatic invasion is less clear. The authors of this report evaluated venous and lymphatic invasion as potential prognostic indicators in patients with CRC focusing on lymph node-negative patients and compared routine and review pathology diagnoses. METHODS: In total, 381 tumors from randomly selected patients were retrospectively reviewed. The presence of vascular invasion was related to disease-free and cancer-specific survival using the Kaplan-Meier method. For multivariable analysis, Cox proportional hazards regression models were performed. RESULTS: Lymphatic invasion and venous invasion were observed in 126 patients (33%) and 87 patients (23%), respectively, and were associated significantly with tumor classification, lymph node status, American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) disease stage, tumor differentiation, pattern of invasion, and extent of tumor budding. The detection of vascular invasion was related to the number of examined tissue blocks. Venous and lymphatic invasion proved to be significant prognostic variables in univariable and multivariable analyses. Extramural vascular involvement was of particular significance. When the analysis was restricted to patients with (AJCC/UICC) stage II disease, venous invasion, but not lymphatic invasion, was identified as an independent prognostic variable. Review pathology diagnoses differed significantly from routine diagnoses with respect to prognostic impact. CONCLUSIONS: Venous and lymphatic invasion proved to be significant prognostic variables in patients with CRC. The detection of vascular invasion and, consequently, risk stratification of affected patients were related to the quality of pathology workup, ie, the number of examined tissue blocks. Observed differences between review and routine pathology diagnoses illustrated the need for high-quality pathology reporting and also for standardized quality control. Cancer 2012;. © 2011 American Cancer Society.